Journal articles on the topic 'HIV, site-specific transmission'
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1
Gelbart, Maoz, and Adi Stern. "Site-Specific Evolutionary Rate Shifts in HIV-1 and SIV." Viruses 12, no. 11 (November 16, 2020): 1312. http://dx.doi.org/10.3390/v12111312.
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Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV.
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SenGupta, Devi, Susan Ribeiro, Henri-Alexandre Michaud, Liyen Loh, Ravi Tandon, R. Jones, Keith Garrison, et al. "Identification of human endogenous retrovirus (HERV-K(HML-2))-specific mucosal CD4+ T cell responses in HIV-1-exposed, seronegative individuals (P6195)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 118.21. http://dx.doi.org/10.4049/jimmunol.190.supp.118.21.
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Abstract The transcriptional silence of human endogenous retroviruses (HERV) can be disrupted in HIV-1 infection. We have reported that the strength of the HERV-specific CD8+ T cell response predicts lower HIV-1 viral load in untreated adults. To determine whether HERV-K immunity plays a role in inhibiting HIV-1 replication at a major site of transmission and CD4+ T cell depletion, we assessed these responses in gut-associated lymphoid tissue (GALT) from rectosigmoid biopsies and blood of HIV-1 exposed, seronegative (HESN) individuals (n=6) by flow cytometry. CMV pp65- and HIV-1 Gag-specific T cells were also measured, and all responses were compared with peripheral antigen-specific responses in uninfected, low-risk controls (n=11). With the exception of stronger CMV-specific CD8+ T cell responses in the HESN group (p=0.024), there were no significant differences between the magnitudes of peripheral antigen-specific T cell responses in the HESN vs. controls. However, HESN subjects had remarkably robust mucosal HIV-1- (median %CD4+cytokine+cells=2.67) and HERV-specific (median %CD4+cytokine+cells=3.41) CD4+ responses, which were much stronger than the corresponding PBMC responses (p=0.0079 and p<0.0001, respectively). These findings suggest that the GALT is an important site of HERV-K expression and immunity in individuals exposed to HIV-1, and should be further investigated in the context of novel vaccine strategies that target conserved antigens such as HERV.
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Doyle, Allison, Claudia Cicala, Katija Jelicic, Donald Van Ryk, Aftab Ahmed Ansari, Anthony S. Fauci, and James Arthos. "Evaluation of a newly developed assay designed to assess the interaction between α4β7 and MAdCAM." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 207.14. http://dx.doi.org/10.4049/jimmunol.196.supp.207.14.
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Abstract HIV infection is characterized by high-level replication in gut-associated lymphoid tissues (GALT). This occurs in part because α4β7 +/CD4+ T cells are a preferred target of HIV infection. α4β7 functions as a gut homing receptor. Homing is mediated through a specific interaction with MAdCAM that is expressed on the surface of the high-endothelial venules that line the gut. In addition, α4β7 binds to the V2 domain of HIV gp120. In an SIV model of HIV mucosal transmission, an antibody specific for α4β7 +was found to prevent infection, but the underlying mechanism for this protection is not fully understood. We have proposed that signaling through α4β7 + facilitates HIV transmission, and that the protection from infection that we observed may reflect the capacity of the anti-α4β7 mAb we employed to interfere with this signaling. In order to investigate the role of α4β7+ signaling in mucosal transmission, we have employed a newly developed adhesion assay (Peachman and Rao) that measures the interaction between either the V2 domain of HIV gp120 or MAdCAM with cells expressing α4β7. We have used this assay to evaluate small molecules and antibody antagonists of these interactions. We have found that small molecule antagonists that bind to the active site in α4β7 abrogate binding of cells to both MAdCAM and the V2 domain of HIV gp120. In addition, we determined that retinoic acid increases the adhesion of MAdCAM and V2 to α4β7 expressing cells. This assay should aid in the development of novel strategies designed to interfere with the trafficking of α4β7 +cells to GALT and to mucosal transmission of HIV.
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Musey, L., Y. Ding, J. Cao, J. Lee, C. Galloway, A. Yuen, K. R. Jerome, and M. J. McElrath. "Ontogeny and Specificities of Mucosal and Blood Human Immunodeficiency Virus Type 1-Specific CD8+ Cytotoxic T Lymphocytes." Journal of Virology 77, no. 1 (January 1, 2003): 291–300. http://dx.doi.org/10.1128/jvi.77.1.291-300.2003.
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ABSTRACT Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at the mucosal site of transmission is poorly understood but crucial in devising strategies to control and prevent infection. To gain further understanding of HIV-1-specific T-cell mucosal immunity, we established HIV-1-specific CD8+ cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix, rectum, and semen of 12 HIV-1-infected individuals and compared their specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood and mucosal CD8+ CTL had common HIV-1 epitope specificities and major histocompatibility complex restriction patterns. Moreover, both systemic and mucosal CTL lysed targets with similar efficiency, primarily through the perforin-dependent pathway in in vitro studies. Sequence analysis of the TCRβ VDJ region revealed in some cases identical HIV-1-specific CTL clones in different compartments in the same HIV-1-infected individual. These results clearly establish that a subset of blood and mucosal HIV-1-specific CTL can have a common origin and can traffic between anatomically distinct compartments. Thus, these effectors can provide immune surveillance at the mucosa, where rapid responses are needed to contain HIV-1 infection.
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Obisesan, Oluwafemi Samuel, Nomathamsanqa Patricia Sithebe, and Hazel Tumelo Mufhandu. "Seroprevalence and characterisation of herpes simplex virus from human immunodeficiency virus in samples collected from two provinces in South Africa: a retrospective study." F1000Research 10 (October 15, 2021): 105. http://dx.doi.org/10.12688/f1000research.28105.3.
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Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions:There is a significant relationship between HSV-2 and HIV-1 in the study population. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
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Obisesan, Oluwafemi Samuel, Nomathamsanqa Patricia Sithebe, and Hazel Tumelo Mufhandu. "Seroprevalence and characterisation of herpes simplex virus from human immunodeficiency virus in samples collected from two provinces in South Africa: a retrospective study." F1000Research 10 (November 17, 2021): 105. http://dx.doi.org/10.12688/f1000research.28105.4.
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Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: There is a significant positive association between HSV-2 and HIV-1 in the study population. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
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Kasting, Christine H., Linda S. Martin, and Robert J. Mullan. "Sharps Disposal Containers: Selection, Evaluation, and Use." Journal of the American Biological Safety Association 2, no. 4 (December 1997): 47–57. http://dx.doi.org/10.1177/109135059700200410.
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Occupational transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) has been documented. The risk of infection with HIV following one needlestick exposure is approximately 0.3% and ranges from 6% to 30% for FMV and from 3.3% to 10% for hepatitis C. The diversity of health care settings makes selection of a single sharps disposal container design inappropriate in many cases. No single sharps disposal container design meets all the disposal containment needs for an entire facility. Selection of any specific container(s) should be based on a comprehensive site-specific hazard analysis. Criteria for the design, selection, and appropriate use of sharps containers were developed. The sharps disposal container safety performance criteria are divided into four areas. First, containers should remain functional during their entire usage. Second, containers must be accessible to workers who use, maintain, or dispose of sharp devices. Third, containers should be visible o the workers who must use them. Last, container designs should provide accommodation to the user, the facility, and the environment. Although engineering controls, such as needleless IV systems and “safety” needles, will reduce injuries, proper selection and use of disposal containers is still important. Prevention strategies include implementation of engineering controls, use of personal protective equipment, training, and the involvement of occupational health professionals and workers.
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Deschambeault, Julie, Jean-Philippe Lalonde, Guillermo Cervantes-Acosta, Robert Lodge, Éric A. Cohen, and Guy Lemay. "Polarized Human Immunodeficiency Virus Budding in Lymphocytes Involves a Tyrosine-Based Signal and Favors Cell-to-Cell Viral Transmission." Journal of Virology 73, no. 6 (June 1, 1999): 5010–17. http://dx.doi.org/10.1128/jvi.73.6.5010-5017.1999.
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ABSTRACT Maturation and release of human immunodeficiency virus type 1 (HIV-1) is targeted at the pseudopod of infected mononuclear cells. However, the intracellular mechanism or targeting signals leading to this polarized viral maturation are yet to be identified. We have recently demonstrated the presence of a functional YXXL motif for specific targeting of HIV-1 virions to the basolateral membrane surface in polarized epithelial Madin-Darby canine kidney cells (MDCK). Site-directed mutagenesis was used to demonstrate that the membrane-proximal tyrosine in the intracytoplasmic tail of the HIV-1 transmembrane glycoprotein (gp41) is an essential component of this signal. In the present study, immunolocalization of viral budding allowed us to establish that this tyrosine-based signal is involved in determining the exact site of viral release at the surface of infected mononuclear cells. Substitution of the critical tyrosine residue was also shown to increase the amount of envelope glycoprotein at the cell surface, supporting previous suggestions that the tyrosine-based motif can promote endocytosis. Although alteration of the dual polarization-endocytosis motif did not affect the infectivity of cell-free virus, it could play a key role in cell-to-cell viral transmission. Accordingly, chronically infected lymphocytes showed a reduced ability to transmit the mutant virus to a cocultivated cell line. Overall, our data indicate that the YXXL targeting motif of HIV is active in various cell types and could play an important role in viral propagation; this may constitute an alternative target for HIV therapeutics and vaccine development.
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Obisesan, Oluwafemi Samuel, Nomathamsanqa Patricia Sithebe, and Hazel Tumelo Mufhandu. "Seroprevalence and characterisation of herpes simplex virus from human immunodeficiency virus in samples collected from two provinces in South Africa: a retrospective study." F1000Research 10 (September 22, 2021): 105. http://dx.doi.org/10.12688/f1000research.28105.2.
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Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: The prevalence of HSV in the population is high with an increased HSV-2 infection in women. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
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Hoorelbeke, Bart, Dana Huskens, Geoffrey Férir, Katrien O. François, Atsushi Takahashi, Kristel Van Laethem, Dominique Schols, Haruo Tanaka, and Jan Balzarini. "Actinohivin, a Broadly Neutralizing Prokaryotic Lectin, Inhibits HIV-1 Infection by Specifically Targeting High-Mannose-Type Glycans on the gp120 Envelope." Antimicrobial Agents and Chemotherapy 54, no. 8 (May 24, 2010): 3287–301. http://dx.doi.org/10.1128/aac.00254-10.
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ABSTRACT The lectin actinohivin (AH) is a monomeric carbohydrate-binding agent (CBA) with three carbohydrate-binding sites. AH strongly interacts with gp120 derived from different X4 and R5 human immunodeficiency virus (HIV) strains, simian immunodeficiency virus (SIV) gp130, and HIV type 1 (HIV-1) gp41 with affinity constants (KD ) in the lower nM range. The gp120 and gp41 binding of AH is selectively reversed by (α1,2-mannose)3 oligosaccharide but not by α1,3/α1,6-mannose- or GlcNAc-based oligosaccharides. AH binding to gp120 prevents binding of α1,2-mannose-specific monoclonal antibody 2G12, and AH covers a broader epitope on gp120 than 2G12. Prolonged exposure of HIV-1-infected CEM T-cell cultures with escalating AH concentrations selects for mutant virus strains containing N-glycosylation site deletions (predominantly affecting high-mannose-type glycans) in gp120. In contrast to 2G12, AH has a high genetic barrier, since several concomitant N-glycosylation site deletions in gp120 are required to afford significant phenotypic drug resistance. AH is endowed with broadly neutralizing activity against laboratory-adapted HIV strains and a variety of X4 and/or R5 HIV-1 clinical clade isolates and blocks viral entry within a narrow concentration window of variation (∼5-fold). In contrast, the neutralizing activity of 2G12 varied up to 1,000-fold, depending on the virus strain. Since AH efficiently prevents syncytium formation in cocultures of persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T lymphocytes, inhibits dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated capture of HIV-1 and subsequent virus transmission to CD4+ T lymphocytes, does not upregulate cellular activation markers, lacks mitogenic activity, and does not induce cytokines/chemokines in peripheral blood mononuclear cell cultures, it should be considered a potential candidate drug for microbicidal use.
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Ferre, April L., Peter W. Hunt, Delandy H. McConnell, Megan M. Morris, Juan C. Garcia, Richard B. Pollard, Hal F. Yee, Jeffrey N. Martin, Steven G. Deeks, and Barbara L. Shacklett. "HIV Controllers with HLA-DRB1*13 and HLA-DQB1*06 Alleles Have Strong, Polyfunctional Mucosal CD4+ T-Cell Responses." Journal of Virology 84, no. 21 (August 18, 2010): 11020–29. http://dx.doi.org/10.1128/jvi.00980-10.
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ABSTRACT A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4+ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8+ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4+ T cells. In this study, we assessed HIV-specific CD4+ T-cell responses in the rectal mucosa of 28 “controllers” (viral load [VL] of <2,000 copies/ml), 14 “noncontrollers” (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had higher-magnitude Gag-specific mucosal CD4+ T-cell responses than individuals on HAART (P < 0.05), as measured by their ability to produce gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and macrophage inflammatory protein 1β (MIP-1β). The frequency of polyfunctional mucosal CD4+ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4+ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4+ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4+ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8+ T-cell response (Spearman's r = 0.43, P = 0.005), suggesting that increased CD4+ T-cell “help” may be important in maintaining strong CD8+ T-cell responses in the gut of HIV controllers.
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Kuebler, Peter J., Megha L. Mehrotra, J. Jeff McConnell, Sara J. Holditch, Brian I. Shaw, Leandro F. Tarosso, Kaitlyn S. Leadabrand, et al. "Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial." Proceedings of the National Academy of Sciences 112, no. 27 (June 22, 2015): 8379–84. http://dx.doi.org/10.1073/pnas.1501443112.
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HIV-1–specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case–control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1–negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19–0.66 and HR = 0.52, 95% CI = 0.28–0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1–specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.
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Kiniry, Brenna, Anupama Ganesh, Peter W. Hunt, Ma Somsouk, Steven G. Deeks, and Barbara L. Shacklett. "Functionality of tissue-resident CD8+ T-cells in the human gastrointestinal tract during chronic HIV-1 infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 149.15. http://dx.doi.org/10.4049/jimmunol.198.supp.149.15.
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Abstract The gastrointestinal tract (GIT) is an important site of HIV transmission and pathogenesis. Preventing or curing HIV infection will likely entail maintenance of protective anti-HIV immune responses in the GIT. Tissue resident memory T-cells (TRM) are long-lived, non-recirculating memory T-cells localized in tissues including the GIT. Positioned near sites of infection, TRM have protective efficacy against several pathogens. The precise role CD8+ TRM in HIV infection is not known. Blood and GIT CD8+ TRM cells from HIV+ and HIV- adults were identified by flow cytrometry using CD45RO, CD69, CD103, S1PR1, T-bet, and Eomesodermin (Eomes). Functionality was assessed in a 6-hour ex vivo stimulation assay. Cells were stimulated with DMSO, Gag, or Staphylococcal Enterotoxin B, and stained for CD107a, IFNγ, Mip-1β, TNFα, and IL-2. The frequency of CD103+CD69+S1PR1− CD8+ T-cells was significantly greater (P=0.005) in gut compared to blood (medians 54.8% and 0.10% respectively), indicative of tissue residency. CD45RO+ cells in this subset were classified as TRM. Consistent with murine studies, CD8+TRM were mainly T-betLowEomesNeg; however a population of EomesHigh CD8+ TRM emerged in HIV+ individuals not on antiretroviral therapy. Although polyfunctional Gag-specific CD8+ TRM responses (CD107a+, IFNγ+, Mip-1β+) appeared strongest in participants who control HIV without therapy (“controllers”), they constituted a smaller proportion of the total rectal Gag-specific CD8+ T-cell response compared to viremic participants not on ART (approximately 15% and 29% respectively). In summary, a large subset of CD8+ T-cells in rectal mucosa are TRM and likely play an important role in HIV-1 containment.
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Locarnini, Stephen, and Nadia Warner. "Major Causes of Antiviral drug Resistance and Implications for Treatment of Hepatitis B virus Monoinfection and Coinfection with HIV." Antiviral Therapy 12, no. 3_suppl (April 1, 2006): 15–23. http://dx.doi.org/10.1177/135965350701203s03.
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The two key events in the life-cycle of the hepatitis B virus (HBV) involve (1) the generation from viral genomic DNA of the covalently closed circular DNA transcriptional template, and (2) the reverse transcription of the viral pregenomic RNA to form the HBV DNA genome. Diversity in the HBV genome is ensured by the low fidelity of the viral reverse transcriptase (rt). Particular selection pressures such as antiviral therapy readily select out escape mutants from this pre-existing quasispecies pool. Antiviral drug resistance in chronic hepatitis B can be caused by many factors, including the viral mutation frequency, the intrinsic mutability of the antiviral target site, the selective pressure exerted by the drug, the magnitude and rate of virus replication, the overall replication fitness of the mutant, the genetic barrier of the >compound and the availability of replication space. In the setting of HIV coinfection, the rate of replication is increased by one to two orders of magnitude, accelerating the emergence of drug resistance in this setting. The HBV genome is arranged into frame-shifted and overlapping reading frames in such a manner that antiviral drug-resistance-associated changes in the rt can result in changes in the viral envelope protein. These HBV isolates with altered surface antigens exhibit reduced binding of specific and neutralizing antibody and so have diagnostic and public health implications, especially in the setting of HIV coinfection where the risk of transmission is increased. Thus, prevention of resistance requires the adoption of strategies that effectively control virus replication, including the use of combination chemotherapy.
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Reynolds, Matthew R., Eva Rakasz, Pamela J. Skinner, Cara White, Kristina Abel, Zhong-Min Ma, Lara Compton, et al. "CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little." Journal of Virology 79, no. 14 (July 2005): 9228–35. http://dx.doi.org/10.1128/jvi.79.14.9228-9235.2005.
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ABSTRACT In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is “too late and too little” to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.
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Quiñones-Mateu, Miguel E., Yong Gao, Sarah C. Ball, Andre J. Marozsan, Awet Abraha, and Eric J. Arts. "In Vitro Intersubtype Recombinants of Human Immunodeficiency Virus Type 1: Comparison to Recent and Circulating In Vivo Recombinant Forms." Journal of Virology 76, no. 19 (October 1, 2002): 9600–9613. http://dx.doi.org/10.1128/jvi.76.19.9600-9613.2002.
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ABSTRACT The increased prevalence of human immunodeficiency virus type 1 (HIV-1) intersubtype recombinants (ISRs) is shaping HIV-1 evolution throughout the world and will have an impact on both therapeutic and vaccine strategies. This study was designed to generate and compare in vitro ISRs to those isolated from HIV-infected individuals throughout the world. Human peripheral blood mononuclear cells were dually infected with seven pairs of HIV-1 isolates from different subtypes (i.e., A to F). Recombinant crossover sites were mapped to specific regions in the envelope (env) gene by using a cloning-hybridization technique and subtype-specific probes. In vitro intersubtype recombination was at least twofold more frequent in the V1-to-V3 region than in any other env fragment, i.e., C1 to V1, V3 to V5, or V5 to gp41. Sequence and recombination site analyses suggested the C2 env domain as a “hot region” for recombination and selection of replication-competent ISRs during the 15-day incubation. In addition to these regional preferences for env recombination, homopolymeric nucleotide tracts, i.e., sequences known to pause reverse transcriptase and promote template switching, were found in most in vitro crossover sites. ISRs, originating from recent dual infections and limited transmission events, partly retained this in vitro regional or sequence preference for recombination sites. However, a shift to crossover sites flanking the gp120-coding sequence was evident in the stable circulating recombinant forms of HIV-1. Based on these findings, HIV-1 recombinants generated from these dual infections may be used as a model for in vivo intersubtype recombination and for the design of various diagnostic assays and vaccine constructs.
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Gardner, Matthew R., Christoph H. Fellinger, Neha R. Prasad, Amber S. Zhou, Hema R. Kondur, Vinita R. Joshi, Brian D. Quinlan, and Michael Farzan. "CD4-Induced Antibodies Promote Association of the HIV-1 Envelope Glycoprotein with CD4-Binding Site Antibodies." Journal of Virology 90, no. 17 (June 22, 2016): 7822–32. http://dx.doi.org/10.1128/jvi.00803-16.
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ABSTRACTThe HIV-1 envelope glycoprotein (Env) is a trimer of gp120/gp41 heterodimers that mediates viral entry. Env binds cellular CD4, an association which stabilizes a conformation favorable to its subsequent association with a coreceptor, typically CCR5 or CXCR4. The CD4- and coreceptor-binding sites serve as epitopes for two classes of HIV-1-neutralizing antibodies: CD4-binding site (CD4bs) and CD4-induced (CD4i) antibodies, respectively. Here we observed that, at a fixed total concentration, mixtures of the CD4i antibodies (E51 or 412d) and the CD4bs antibody VRC01 neutralized the HIV-1 isolates 89.6, ADA, SG3, and SA32 more efficiently than either antibody alone. We found that E51, and to a lesser extent 412d and 17b, promoted association of four CD4bs antibodies to the Env trimer but not to monomeric gp120. We further demonstrated that the binding of the sulfotyrosine-binding pocket by CCR5mim2-Ig was sufficient for promoting CD4bs antibody binding to Env. Interestingly, the relationship is not reciprocal: CD4bs antibodies were not as efficient as CD4-Ig at promoting E51 or 412d binding to Env trimer. Consistent with these observations, CD4-Ig, but none of the CD4bs antibodies tested, substantially increased HIV-1 infection of a CD4-negative, CCR5-positive cell line. We conclude that the ability of CD4i antibodies to promote VRC01 association with Env trimers accounts for the increase potency of VRC01 and CD4i antibody mixtures. Our data further suggest that potent CD4bs antibodies avoid inducing Env conformations that bind CD4i antibodies or CCR5.IMPORTANCEPotent HIV-1-neutralizing antibodies can prevent viral transmission and suppress an ongoing infection. Here we show that CD4-induced (CD4i) antibodies, which recognize the conserved coreceptor-binding site of the HIV-1 envelope glycoprotein (Env), can increase the association of Env with potent broadly neutralizing antibodies that recognize the CD4-binding site (CD4bs antibodies). We further show that, unlike soluble forms of CD4, CD4bs antibodies poorly induce envelope glycoprotein conformations that efficiently bind CCR5. This study provides insight into the properties of potent CD4bs antibodies and suggests that, under some conditions, CD4i antibodies can improve their potency. These observations may be helpful to the development of vaccines designed to elicit specific antibody classes.
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Santelli, John S., Anne-Emanuelle Birn, and James Linde. "School Placement for Human Immunodeficiency Virus-Infected Children: The Baltimore City Experience." Pediatrics 89, no. 5 (May 1, 1992): 843–48. http://dx.doi.org/10.1542/peds.89.5.843.
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Over the past 6 years, the city of Baltimore has successfully implemented a school placement policy for human immunodeficiency virus (HIV)-infected children and children with acquired immiunodeficiency syndrome (AIDS). Both policy and specific procedures are based on nationally promulgated guidelines. School placement policy is part of an overall AIDS policy that includes education of students and staff and adoption of universal precautions to prevent transmission of communicable diseases in school. Implementation has been marked by excellent collaboration between the departments of health and education. Important policy components include expedited clinical investigation of each case, an interagency review panel, strict protection of confidentiality, a restricted setting for certain children, a school site visit for each placement, and continued monitoring of the school placement by school nurses. Many HIV-infected students need special educational services and/or school health services. The Baltimore City school placement process has avoided the exaggerated publicity endured by some communities, where media reporting has aggravated community fears and invaded the lives of families with HIV-infected children. Baltimore City has succeeded in ensuring access to education, protecting families' confidentiality, and providing special care for HIV-infected students. Local communities should emphasize national guidelines in designing school placement policies for HIV-infected children. School placement policies work best in the context of a comprehensive policy incorporating AIDS education and care.
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Elinder, Malin, Helena Nordström, Matthis Geitmann, Markku Hämäläinen, Lotta Vrang, BO Öberg, and U. Helena Danielson. "Screening for NNRTIs with Slow Dissociation and High Affinity for a Panel of HIV-1 RT Variants." Journal of Biomolecular Screening 14, no. 4 (April 2009): 395–403. http://dx.doi.org/10.1177/1087057109333977.
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A lead optimization library consisting of 800 HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) was screened in parallel against 4 clinically relevant variants of HIV-1 RT (Wt, L100I, Y181C, and K103N) using a surface plasmon resonance—based biosensor. The aim was to identify inhibitors suitable in specific topical microbicides efficient for preventing the transmission of a range of clinically significant strains of HIV-1. The authors hypothesized that such compounds should have high affinity and slow dissociation rates for multiple variants of the target. To efficiently analyze the large amount of real-time data (sensorgrams) that were generated in the screening, they initially used signals from 3 selected time points to identify compounds with high affinity and slow dissociation for the complete panel of enzyme variants. Hits were confirmed by visually inspecting the complete sensorgrams. Two structurally unrelated compounds fulfilled the hit criteria, but only 1 compound was found to (a) compete with a known NNRTI for binding to the NNRTI site, (b) inhibit HIV-1 RT activity, and (c) inhibit HIV-1 replication in cell culture, for all 4 enzyme variants. This novel screening methodology offers high-resolution real-time kinetic data for multiple targets in parallel. It is expected to have broad applicability for the discovery of compounds with defined kinetic profiles, crucial for optimal therapeutic effects. ( Journal of Biomolecular Screening 2009:395-403)
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Oliver, Cassandra, Peter Rebeiro, Bryan Shepherd, Jeanne Keruly, Kenneth Mayer, Christopher Matthews, Bulant Turan, et al. "3309 Clinic-Level Factors and Retention in Care among People Living with HIV (PLWH) in a United States (US) Multi-Site Cohort, 2010-2016." Journal of Clinical and Translational Science 3, s1 (March 2019): 85–86. http://dx.doi.org/10.1017/cts.2019.197.
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OBJECTIVES/SPECIFIC AIMS: The National HIV/AIDS strategy aims to increase retention in care (RIC) to reduce HIV transmission and mortality. Previous studies have evaluated clinic-level interventions such as appointment reminders and peer navigation. However, few studies have investigated the association between multiple clinic-level factors and RIC among PLWH across the United States. We conducted a multi-site cohort study to identify clinic-level factors associated with RIC in the United States from 2010-2016. METHODS/STUDY POPULATION: We included PLWH with at least one HIV primary care visit from 2010-2016 at seven sites of the Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS). Individual-level data collected as part of routine clinical care were abstracted from the electronic health record. Clinic-level data were gathered through a survey and included questions on site characteristics (i.e. clinic volume) as well as services available at the site during each year of the study: peer navigation, RIC posters/brochures, laboratory test timing, flexible scheduling, appointment reminder types, and stigma support services defined as intensive HIV education and advocacy regarding support to address stigma at outreach visits. RIC was defined as ≥2 encounters per year, ≥90 days apart, observed until death, administrative censoring (December 31, 2016), or loss to follow-up (no visit for >12 months with no future visits). Poisson panel regression with robust error variance, clustering by site and adjusting for calendar year, age (modeled with a cubic spline), sex, race/ethnicity, and HIV transmission risk factor, was used to estimate incident rate ratios (IRR) with 95% confidence intervals (CI) for RIC. Clustering by site has been shown to absorb for clustering that could occur at the individual level as well. RESULTS/ANTICIPATED RESULTS: Among 21,046 patients contributing 103,348 person-years, 67% of person-years were RIC. Text appointment reminders (IRR = 1.13; 95% CI: 1.03-1.24) and stigma support services (IRR=1.11; 95% CI:1.04-1.19) were significantly associated with RIC. RIC disparities in individual-level patient characteristics were observed even after accounting for clinic-level characteristics. Older patients were more likely to be RIC demonstrated through year comparisons due to the use of a spline; for age 50 years (IRR = 1.07, 95% CI: 1.06-1.08) and 60 years (IRR = 1.15, 95% CI: 1.13-1.17) compared to 45 years. Female PLWH were more likely to be RIC compared to males (IRR = 1.03, 95% CI: 1.02-1.05) and Hispanic PLWH were more likely to be RIC compared to white, non-Hispanic PLWH (IRR = 1.09, 95% CI: 1.05-1.13). Although commonly found to be associated with worse RIC, Black race and injection drug use were not associated with RIC in this population. DISCUSSION/SIGNIFICANCE OF IMPACT: In this multi-site US cohort study from 2010-2016, availability of text appointment reminders and stigma support services at a clinic were associated with approximately 10% higher probability of RIC than at clinics without those services. RIC disparities persisted with respect to individual-level characteristics of age, sex, and race/ethnicity even after accounting for these clinic-level factors. Prospective studies examining the impact of these clinic-level factors and individual-level uptake of these services on RIC are needed.
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Warren, Cody J., Nicholas R. Meyerson, Alex C. Stabell, Will T. Fattor, Gregory K. Wilkerson, and Sara L. Sawyer. "A glycan shield on chimpanzee CD4 protects against infection by primate lentiviruses (HIV/SIV)." Proceedings of the National Academy of Sciences 116, no. 23 (May 21, 2019): 11460–69. http://dx.doi.org/10.1073/pnas.1813909116.
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Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzee-specific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virus-binding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses.
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Brown, Tyler S., Lavanya Challagundla, Evan H. Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C. Auld, N. Sarita Shah, et al. "Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa." Proceedings of the National Academy of Sciences 116, no. 46 (October 28, 2019): 23284–91. http://dx.doi.org/10.1073/pnas.1906636116.
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Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.
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Crothers, Kristina, Kieran R. Daly, David Rimland, Matthew Bidwell Goetz, Cynthia L. Gibert, Adeel A. Butt, Amy C. Justice, Kpandja Djawe, Linda Levin, and Peter D. Walzer. "Decreased Serum Antibody Responses to RecombinantPneumocystisAntigens in HIV-Infected and Uninfected Current Smokers." Clinical and Vaccine Immunology 18, no. 3 (December 29, 2010): 380–86. http://dx.doi.org/10.1128/cvi.00421-10.
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ABSTRACTSerologic studies can provide important insights into the epidemiology and transmission ofPneumocystis jirovecii. Exposure toP. jiroveciican be assessed by serum antibody responses to recombinant antigens from the major surface glycoprotein (MsgC), although factors that influence the magnitude of the antibody response are incompletely understood. We determined the magnitudes of antibody responses toP. jiroveciiin comparison to adenovirus and respiratory syncytial virus (RSV) in HIV-infected and uninfected patients and identified predictors associated with the magnitude of the response. We performed a cross-sectional analysis using serum samples and data from 153 HIV-positive and 92 HIV-negative subjects enrolled in a feasibility study of the Veterans Aging Cohort 5 Site Study (VACS 5). Antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Independent predictors of antibody responses were determined using multivariate Tobit regression models. The results showed that serum antibody responses toP. jiroveciiMsgC fragments were significantly and independently decreased in current smokers. Antibodies toP. jiroveciialso tended to be lower with chronic obstructive pulmonary disease (COPD), hazardous alcohol use, injection drug use, and HIV infection, although these results were not statistically significant. These results were specific toP. jiroveciiand did not correlate with adenovirus. Antibody responses to RSV were in the inverse direction. Thus, current smoking was independently associated with decreasedP. jiroveciiantibody responses. Whether smoking exerts an immunosuppressive effect that affects theP. jiroveciiantibody response, colonization, or subsequent risk for disease is unclear; prospective, longitudinal studies are needed to evaluate these findings further.
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Acheampong, Edward A., Zahida Parveen, Lois W. Muthoga, Vivian Wasmuth-Peroud, Mehrnush Kalayeh, Adnan Bashir, Robert Diecidue, Muhammad Mukhtar, and Roger J. Pomerantz. "Molecular Interactions of Human Immunodeficiency Virus Type 1 with Primary Human Oral Keratinocytes." Journal of Virology 79, no. 13 (July 1, 2005): 8440–53. http://dx.doi.org/10.1128/jvi.79.13.8440-8453.2005.
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ABSTRACT Infection of the oral mucosa of human immunodeficiency virus type 1 (HIV-1)-infected individuals remains an under-evaluated and somewhat enigmatic process. Nonetheless, it is of profound importance in the ongoing AIDS pandemic, based on its potential as a site of person-to-person transmission of the virus as well as a location of HIV-1 pathogenesis and potential reservoir of disease in the setting of virally suppressive highly active antiretroviral therapy. We utilized molecular and virological techniques to analyze HIV-1 infection of primary human mucosal cells and also evaluated the proapoptotic potential of selected HIV-1 proteins in primary isolated human oral keratinocytes. Primary isolated human oral keratinocytes were plated on 0.4 μM polyethylenetetraphthalate cell culture inserts to form an in vitro oral mucosal layer. The strength of this layer in forming a barrier was determined by measuring trans-epithelial electrical current passage across the monolayer. The oral keratinocyte monolayers had trans-epithelial electrical resistance of approximately 176 to 208 Ω. For viral infectivity assays, the macrophage-tropic (R5) HIV-1 strains, YU-2 and ADA, and T-cell-line-tropic (X4), NL4-3 virions, incubated with or without deoxynucleoside triphosphates (dNTPs) and/or the polyamines spermine and spermidine, were used to infect oral keratinocytes. Of importance, polyamines and dNTPs have been shown to enhance natural endogenous reverse transcription (NERT), a step essential for early lentiviral infection, and are abundantly present in human semen. The infectivities of HIV-1 strains YU-2, ADA, and NL4-3 for these primary keratinocytes were dramatically increased by the addition of physiological concentrations of dNTPs, spermine, and spermidine. Binding and viral internalization assay studies showed no differences in these oral mucosal cells, with or without NERT-altering agents. It was also observed that the recombinant, cell-free HIV-1 proteins Nef, Tat, and gp120 (R5) induced apoptosis in primary oral keratinocytes compared with the results seen with nontreated cells or cells treated with glutathione S-transferase protein as a control under similar conditions. Microarray analyses suggested that HIV-1 gp120 and Tat induce apoptosis in primary human oral keratinocytes via the Fas/FasL apoptotic pathway, whereas induction of apoptosis by Nef occurs through both Fas/FasL and mitochondrial apoptotic pathways. Thus, these findings suggest molecular mechanisms by which semen in particular, as well as other bodily fluids such as cervicovaginal secretions, could increase oral transmission of HIV-1 via increasing infectivity in confluent and low-replicating oral keratinocytes. As well, the induction of apoptosis in human oral keratinocytes with relevant HIV-1-specific proteins suggests another potential complementary mechanism by which the oral mucosa barrier may be disrupted during HIV-1 infection in vivo.
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Stuccio, Sarah, Rakhshanda Akram, and Lisa A. Spacek. "1541. Prevalence of Asymptomatic Sexually Transmitted Infections (STIs) in a Philadelphia Ryan White HIV population." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S770. http://dx.doi.org/10.1093/ofid/ofaa439.1721.
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Abstract Background In 2018, Philadelphia County ranked 7th, 8th and 16th for chlamydia (CT), gonorrhea (GC), and syphilis cases, respectively, in the Centers for Disease Control (CDC) STI Surveillance Report. Asymptomatic presentations and lack of routine screening, especially at extragenital (i.e., pharyngeal and rectal) sites, increase the challenge of timely diagnosis and treatment. We determined extent of screening, reported symptoms, and asymptomatic infections. Methods We analyzed records of 372 patients receiving care at an urban, university-based Ryan White HIV clinic from 2016-2018. Outcomes included: positive GC/CT nucleic acid amplification tests from genital, pharyngeal, and rectal sites as well as new diagnoses of syphilis. We collected demographic data, risk factors for HIV transmission, time from HIV diagnosis, number of clinic visits, multiple sex partners, partner with STI, and injection drug use. We used logistic regression to model factors associated with STIs and determined prevalence of asymptomatic STIs. Results Of 372 participants, 234 (63%) were men, 262 (70%) were Black, 245 (66%) were over 40 years old, 148 (40%) identified as MSM, 140 (38%) reported inconsistent condom use, 89 (24%) reported multiple sex partners, 35 (9%) reported injection drug use, 141 (38%) had past STI, and 26 (7%) had partner with past STI. Mean time from HIV diagnosis was 12.3 years (SD, 8.8) and mean number of clinic visits was 2/year. Testing included 720 GC/CT urine, 176 GC/CT pharyngeal, 143 GC/CT rectal swabs and 887 syphilis blood tests. Asymptomatic GC/CT infections were seen in urine 6/22 (27%), pharyngeal 12/14 (86%) and rectal 28/31 (90%) swabs. And, of 39 new diagnoses of syphilis, 23 (59%) were asymptomatic. In multivariate analysis, men (aOR, 12.2, 95%CI, 2.7-55.3), < 40 years (3.2, 1.7-6.1), with clinic visit in 2018 (1.4, 1.2-1.8), and partner with STI (1.7, 0.9-2.8) were more likely to have a positive GC/CT test. Patients with positive syphilis test were more likely men (4.6, 1.1-20.2), with multiple sex partners (3.7, 1.7-8.0), and more recent HIV diagnosis (1.1, 1.0-1.1). Prevalence of Asymptomatic STIs Conclusion Results indicate the importance of routine, site-specific STI screening among patients living with HIV. Our findings can inform screening strategies among urban HIV populations. Disclosures All Authors: No reported disclosures
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Guiraud, Jennifer, Manon Lounnas, Anne Boissière, Chloé Le Roy, Eric Elguero, Anne Laure Banuls, Cécile Bébéar, Sylvain Godreuil, and Sabine Pereyre. "Lower mgpB diversity in macrolide-resistant Mycoplasma genitalium infecting men visiting two sexually transmitted infection clinics in Montpellier, France." Journal of Antimicrobial Chemotherapy 76, no. 1 (October 20, 2020): 43–47. http://dx.doi.org/10.1093/jac/dkaa410.
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Abstract Objectives Men engaged in high-risk sexual behaviour, such as MSM, are likely to be infected by resistant Mycoplasma genitalium strains. Understanding the transmission dynamics is challenging. We aimed to investigate the molecular epidemiology of M. genitalium in men visiting sexually transmitted infection (STI) clinics. Patients and methods Between June 2017 and February 2018, 95 M. genitalium-positive specimens from 78 men, including 76.9% MSM, visiting two STI clinics in Montpellier, France, were analysed for SNPs in the mgpB adhesin gene and number of tandem repeats in the MG_309 gene. Macrolide and fluoroquinolone resistance were determined. Typing results were compared with antibiotic resistance, sexual behaviour, sampling site, HIV pre-exposure prophylaxis (PrEP) usage and HIV status. Results Thirty-eight mgpB STs were identified, including 23 new STs, with ST4 being most prevalent. The mgpB/MG_309 typing method identified 52 genetic profiles, resulting in a discriminatory index of 0.979. Macrolide and fluoroquinolone resistance-associated mutations were detected in 58.3% and 10.8% of patients, respectively. The macrolide resistance rate was higher among MSM than among men who have sex with women only (68.4% versus 9.1%; adjusted OR, 1.57; 95% CI, 1.13–2.18; P = 0.007). A lower mgpB diversity of 0.870 was found among macrolide-resistant strains in comparison with 0.978 in macrolide-susceptible strains, with an over-representation of mgpB ST62 and ST153. Conclusions Although macrolide resistance spread appears polyclonal in M. genitalium, the lower diversity of mgpB types among macrolide-resistant strains may reflect the easier spread of a few specific mgpB types or the occurrence of sexual networks among MSM.
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Trapecar, Martin, Benjamin Cohen, Shahzada Khan, Erik Woodruff, Julie Luong, and Shomyseh Sanjabi. "Generation of colonic T-cell mediated protective immunity after rectal infection with LCMV." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 208.16. http://dx.doi.org/10.4049/jimmunol.196.supp.208.16.
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Abstract How viral-specific immunity is generated in the colon is not well understood, leaving a major gap in our knowledge of defining the parameters needed to develop vaccines against rectally transmitted pathogens. Clearance of most intracellular pathogens requires CD8 T cells, and since unlike the small intestine, the colon lacks organized lymphoid aggregates such as Peyer’s patches, generating protective immunity requires a series of orchestrated events to mobilize CD8 T cells to this mucosal organ. Complicating the generation of protective immunity is the fact that the colon naturally serves as an inductive site for tolerance against many commensal organisms and food antigens. Our central hypothesis, supported by our data, is that the tolerogenic nature of the colon limits induction of robust inflammatory responses needed to activate CD8 T cells for their efficient and timely recruitment to the colonic mucosa. We are using our newly established lymphocytic choriomeningitis virus (LCMV) rectal infection model to determine why CD8 T-cell priming is sub-optimal after rectal viral transmission of LCMV and why the activated CD8 T cells are unable to control the virus from spreading systemically. We are employing several genetic tools to ablate various monocytic and dendritic cell populations to determine their specific role in promoting CD8 T cell priming, activation, differentiation, and migration after rectal LCMV infection. This knowledge is required to break down barriers that have prevented development of successful T-cell-mediated vaccines against sexually transmitted RNA viruses, such as HIV, and will ultimately support the development of vaccines against sexually transmitted infections.
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Rebeiro, Peter F., Peter F. Rebeiro, Cathy Jenkins, Aihua Bian, Jordan Lake, Jordan Lake, Kassem Bourgi, et al. "LB9. The Effect of Initiating Integrase Inhibitor-based vs. Non-Nucleoside Reverse Transcriptase Inhibitor-based Antiretroviral Therapy on Progression to Diabetes among North American Persons in HIV Care." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S996—S997. http://dx.doi.org/10.1093/ofid/ofz415.2492.
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Abstract Background Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been implicated in greater weight gain than other regimens among people with HIV, but there is little evidence about its role in serious clinical outcomes proximal to weight gain. We therefore examined the impact of initial ART regimen class/drug on incident diabetes mellitus (DM) in a large North American HIV cohort. Methods Treatment-naïve adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART from January 2007 to December 2016 in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Individuals were followed until date of incident DM (HgA1c >6.5%, diabetes-specific medication, DM diagnosis along with diabetes-related medication, or random glucose measure ≥200 mg/dL), virologic failure, regimen core switch, cohort close (through December 2016), death date, or loss to follow-up (≥12 months with no contact before cohort close). Cox regression stratified by site and adjusting for age, sex, race, HIV transmission risk, year of ART initiation, and baseline weight, CD4+ cell count, and HIV-1 RNA yielded adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident DM by ART class and INSTI drug. Results Among 21,516 eligible ART initiators, 10,553 (49%) started NNRTIs, 6,677 (31%) PIs, and 4,286 (20%) INSTIs, with median follow-up of 3.0, 2.4, and 1.6 years, respectively. Among INSTI initiators, 21% started dolutegravir (DTG), 28% raltegravir (RAL), and 51% elvitegravir (EVG). Overall, 669 (3%) developed DM. Patients differed by all characteristics except baseline body mass index and HIV-1 RNA. Those starting INSTIs vs. NNRTIs had increased risk of incident DM (HR = 1.22; CI: 0.95–1.57) similar in magnitude as for PI vs. NNRTI initiators (HR = 1.25; CI: 1.05–1.49) (figure). Among INSTIs, starting RAL- vs. NNRTI-based ART was associated with a 50% increased risk of DM (HR = 1.50, CI: 1.11–2.03). Conclusion Initiating ART with INSTI- or PI- vs. NNRTI-based regimens may confer increased risk of incident DM, though risk is heterogeneous among INSTIs. Further research is needed to determine whether this elevated risk can be attributed to weight gain. Disclosures Kassem Bourgi, MD, Gilead Sciences (Grant/Research Support), Joseph J. Eron, MD, Gilead Sciences (Consultant, Grant/Research Support), Janssen (Grant/Research Support), Merck (Consultant), ViiV Healthcare (Consultant, Grant/Research Support), M. John Gill, MB, ChB, MSc, Gilead (Board Member), Merck (Board Member), Viiv (Board Member), Michael Silverberg, PhD, MPH, Gilead (Grant/Research Support). Other Authors: No reported disclosures.
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Weiss, Kayla A., Christopher Petro, Betsy C. Herold, and William R. Jacobs. "Herpes simplex virus-2 ΔgD vaccination primes robust cellular immunity with memory Th17 cell recall following challenge." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 146.3. http://dx.doi.org/10.4049/jimmunol.196.supp.146.3.
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Abstract Approximately 25 percent of women are infected with herpes simplex virus (HSV)-2 in the United States. Even with anti-viral treatments, the rate of HSV transmission has increased 30 percent in the last 20 years. Furthermore the risk of acquiring an HIV infection increases 2–4 fold for HSV-2-infected individuals. Therefore, the need to have an FDA-approved HSV vaccine is immediate. Recently we have developed a single-cycle HSV-2 vaccine strain genetically deficient in glycoprotein D (HSV-2 ΔgD). Complete protection from disease and the establishment of latency is observed following either HSV-1 or HSV-2 challenge of HSV-ΔgD-vaccinated mice. We have also previously demonstrated that HSV-2 ΔgD elicits a protective, broadly functional antibody response. We hypothesized that HSV-2 ΔgD vaccination also primed T cell immunity, contributing to vaccine-induced protection. We observe both CD4 and CD8 T cells are activated by vaccination, and contract to establish a stable memory population. Vaccine-induced memory CD8 T cells are polyfunctional cytokine-producers with 55 percent specific for the immunodominant HSV gB498-505 epitope. Memory CD4 T cells primed by vaccination are quickly recalled to the infection site following challenge and exhibit a Th17-dominant phenotype with 60 percent of recalled cells producing IL-17A. We also determined that CD4 T cell help is required to stabilize the germinal center B cell population and to elicit protective antibodies following vaccination. Together, our data demonstrate HSV-2 ΔgD vaccination induces robust cellular, as well as humoral, immunity and likely an ideal vaccine vector.
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Ware, Chelsea, Andrew D. Sparks, Matthew E. Levy, Hilary Wolf, and Marc O. Siegel. "105. Null Effect of Financial Incentives or Social Media Support on Prep Adherence in a Randomized Controlled Trial of Young Men Who Have Sex with Men of Colour." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S181—S182. http://dx.doi.org/10.1093/ofid/ofaa439.415.
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Abstract Background Pre-exposure prophylaxis (PrEP) using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) effectively reduces HIV transmission, with efficacy being dependent on adherence. We evaluated the effect of either social media-based support or financial incentives on PrEP adherence among young MSM of color in Washington, DC Methods MSM aged 18–29 were randomized 1:1:1 to standard of care (SOC) PrEP (Control group), SOC PrEP + invitation to a bidirectional Facebook group supervised by two clinicians (Social Media group), or SOC PrEP + $50 gift card at each of two follow-up visits (Financial Incentive group). Participants were asked to return at 3 and 6 months. Adherence was monitored with predefined dried blood spots (DBS) TFVdp levels with < 490, 490–979, 980–1749 and ≥1750 fmol/punch correlating with average of < 2, 2–4, 4–6, and 7 doses per week Results We enrolled 53 MSM. Average age was 22.5 years and 72% of participants were Black. At enrollment, 96% had previously heard of PrEP, 17% had ever taken PrEP but none had taken PrEP in the prior 6 months. 92% of participants reported condomless anal sex in the prior 3 months, 36% with an HIV-positive man or man of unknown HIV status (Table 1). 81% of participants returned for their 3-month visit and 70% for their 6-month visit. Mean self-reported PrEP adherence over the previous 3 months was 78% with no difference in adherence between the three groups at either visit. Based on DBS TFVdp levels, protective PrEP adherence (≥4 doses/week) was measured in 46% of the Financial Incentive group and in 57% of the Social Media group compared to in 67% of the Control group (p=0.38). Only 16% of TFVdp levels corresponded to taking PrEP 7 days a week (Figure 1). There was no change in sexual risk activity over the course of the study. 38 sexually transmitted infections were diagnosed in 26 participants (Figure 2). No participant tested positive for HIV. 3 months after study completion, 9 participants were still taking PrEP Table I. Sexual risk behaviors over the previous 3 months for study participants assessed at baseline visit, as well as 3 month and 6 month follow up visits Figure 1. PrEP Adherence. Figure 2. Number of sexually transmitted infections by specific etiology and site diagnosed Conclusion Our study showed no impact of either offering financial incentives or providing access to a supervised Facebook-based support group on PrEP adherence. Financial compensation based on level of PrEP adherence and using a more age-appropriate social media platform may have a greater impact on adherence Disclosures All Authors: No reported disclosures
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Berre, Stefano, Raphaël Gaudin, Bruna Cunha de Alencar, Marion Desdouits, Mélanie Chabaud, Nadia Naffakh, Marc Rabaza-Gairi, François-Xavier Gobert, Mabel Jouve, and Philippe Benaroch. "CD36-specific antibodies block release of HIV-1 from infected primary macrophages and its transmission to T cells." Journal of Experimental Medicine 210, no. 12 (October 21, 2013): 2523–38. http://dx.doi.org/10.1084/jem.20130566.
Full textAbstract:
HIV-1–infected macrophages likely represent viral reservoirs, as they accumulate newly formed virions in internal virus-containing compartments (VCCs). However, the nature and biogenesis of VCCs remain poorly defined. We show that upon HIV-1 infection of primary human macrophages, Gag is recruited to preexisting compartments containing the scavenger receptor CD36, which then become VCCs. Silencing of CD36 in HIV-1–infected macrophages decreases the amount of virions released. Strikingly, soluble anti-CD36 antibodies, but not the natural ligands of CD36, inhibit release of virions from HIV-1–infected macrophages and the transmission of virus to CD4+ T cells. The effect of the antibodies is potent, rapid, and induces the retention of virions within VCCs. Ectopic expression of CD36 in HeLa cells renders them susceptible to the inhibitory effect of the anti-CD36 mAb upon HIV-1 infection. We show that the anti-CD36 mAb inhibits HIV-1 release by clustering newly formed virions at their site of budding, and that signaling via CD36 is not required. Thus, HIV-1 reservoirs in macrophages may be tackled therapeutically using anti-CD36 antibodies to prevent viral dissemination.
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Crombie, René, Roy L. Silverstein, Clarinda MacLow, S. Frieda A. Pearce, Ralph L. Nachman, and Jeffrey Laurence. "Identification of a CD36-related Thrombospondin 1–binding Domain in HIV-1 Envelope Glycoprotein gp120: Relationship to HIV-1–specific Inhibitory Factors in Human Saliva." Journal of Experimental Medicine 187, no. 1 (January 5, 1998): 25–35. http://dx.doi.org/10.1084/jem.187.1.25.
Full textAbstract:
Human and non–human primate salivas retard the infectivity of HIV-1 in vitro and in vivo. Because thrombospondin 1 (TSP1), a high molecular weight trimeric glycoprotein, is concentrated in saliva and can inhibit the infectivity of diverse pathogens in vitro, we sought to determine the role of TSP1 in suppression of HIV infectivity. Sequence analysis revealed a TSP1 recognition motif, previously defined for the CD36 gene family of cell adhesion receptors, in conserved regions flanking the disulfide-linked cysteine residues of the V3 loop of HIV envelope glycoprotein gp120, important for HIV binding to its high affinity cellular receptor CD4. Using solid-phase in vitro binding assays, we demonstrate direct binding of radiolabeled TSP1 to immobilized recombinant gp120. Based on peptide blocking experiments, the TSP1–gp120 interaction involves CSVTCG sequences in the type 1 properdin-like repeats of TSP1, the known binding site for CD36. TSP1 and fusion proteins derived from CD36-related TSP1-binding domains were able to compete with radiolabeled soluble CD4 binding to immobilized gp120. In parallel, purified TSP1 inhibited HIV-1 infection of peripheral blood mononuclear cells and transformed T and promonocytic cell lines. Levels of TSP1 required for both viral aggregation and direct blockade of HIV-1 infection were physiologic, and affinity depletion of salivary TSP1 abrogated >70% of the inhibitory effect of whole saliva on HIV infectivity. Characterization of TSP1–gp120 binding specificity suggests a mechanism for direct blockade of HIV infectivity that might be exploited to retard HIV transmission that occurs via mucosal routes.
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Bose, Purabi Deka, Bhudev Chandra Das, Rajib Kishore Hazam, Ashok Kumar, Subhash Medhi, and Premashis Kar. "Evidence of extrahepatic replication of hepatitis E virus in human placenta." Journal of General Virology 95, no. 6 (June 1, 2014): 1266–71. http://dx.doi.org/10.1099/vir.0.063602-0.
Full textAbstract:
The incidence and severity of hepatitis E virus (HEV) infection in pregnant women is high in developing countries. Transplacental transmission of HEV in the third trimester of pregnancy has been found to be associated with high fetal mortality. Based on this evidence and in the absence of reports on HEV replication in extrahepatic sites, this study was carried out to investigate if HEV replication occurs in the placenta of infected mothers. The study included 68 acute viral hepatitis (AVH) and 22 acute liver failure (ALF) pregnant patients. Viral RNA was extracted from blood and placenta. HEV replication in placenta was confirmed by a replicative negative-strand-specific reverse transcriptase PCR. Viral load was estimated by real-time PCR. Immunohistochemical studies were also carried out for in situ detection of HEV in placental tissue sections. Replicative HEV RNA was detectable only in the placenta in ALF and AVH cases and not in blood samples. Positive staining of placental tissue sections with HEV antibody against the viral structural protein ORF3 was observed. HEV replication in placenta also correlated with fetal and maternal mortality in ALF patients. It is demonstrated for the first time that HEV replication occurs in human placenta and that placenta may be a site of extrahepatic replication of HEV in humans.
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Laing, Eric D., Chanakha K. Navaratnarajah, Sofia Cheliout Da Silva, Stephanie R. Petzing, Yan Xu, Spencer L. Sterling, Glenn A. Marsh, et al. "Structural and functional analyses reveal promiscuous and species specific use of ephrin receptors by Cedar virus." Proceedings of the National Academy of Sciences 116, no. 41 (September 23, 2019): 20707–15. http://dx.doi.org/10.1073/pnas.1911773116.
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Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.
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Mathiesen, Christian K., Jannick Prentoe, Luke W. Meredith, Tanja B. Jensen, Henrik Krarup, Jane A. McKeating, Judith M. Gottwein, and Jens Bukh. "Adaptive Mutations Enhance Assembly and Cell-to-Cell Transmission of a High-Titer Hepatitis C Virus Genotype 5a Core-NS2 JFH1-Based Recombinant." Journal of Virology 89, no. 15 (May 20, 2015): 7758–75. http://dx.doi.org/10.1128/jvi.00039-15.
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ABSTRACTRecombinant hepatitis C virus (HCV) clones propagated in human hepatoma cell cultures yield relatively low infectivity titers. Here, we adapted the JFH1-based Core-NS2 recombinant SA13/JFH1C3405G,A3696G(termed SA13/JFH1orig), of the poorly characterized genotype 5a, to Huh7.5 cells, yielding a virus with greatly improved spread kinetics and an infectivity titer of 6.7 log10focus-forming units (FFU)/ml. We identified several putative adaptive amino acid changes. In head-to-head infections at fixed multiplicities of infection, one SA13/JFH1origmutant termed SA13/JFH1Core-NS5B, containing 13 amino acid changes (R114W and V187A [Core]; V235L [E1]; T385P [E2]; L782V [p7]; Y900C [NS2]; N2034D, E2238G, V2252A, L2266P, and I2340T [NS5A]; A2500S and V2841A [NS5B]), displayed fitness comparable to that of the polyclonal high-titer adapted virus. Single-cycle virus production assays in CD81-deficient Huh7-derived cells demonstrated that these changes did not affect replication but increased HCV assembly and specific infectivity as early as 24 h posttransfection. Infectious coculture assays in Huh7.5 cells showed a significant increase in cell-to-cell transmission for SA13/JFH1Core-NS5Bviruses as well as viruses with only p7 and nonstructural protein mutations. Interestingly, the E2 hypervariable region 1 (HVR1) mutation T385P caused (i) increased sensitivity to neutralizing patient IgG and human monoclonal antibodies AR3A and AR4A and (ii) increased accessibility of the CD81 binding site without affecting the usage of CD81 and SR-BI. We finally demonstrated that SA13/JFH1origand SA13/JFH1Core-NS5B, with and without the E2 mutation T385P, displayed similar biophysical properties following iodixanol gradient ultracentrifugation. This study has implications for investigations requiring high virus concentrations, such as studies of HCV particle composition and development of whole-virus vaccine antigens.IMPORTANCEHepatitis C virus (HCV) is a major global health care burden, affecting more than 150 million people worldwide. These individuals are at high risk of developing severe end-stage liver diseases. No vaccine exists. While it is possible to produce HCV particles resembling isolates of all HCV genotypes in human hepatoma cells (HCVcc), production efficacy varies. Thus, for several important studies, including vaccine development,in vitrosystems enabling high-titer production of diverse HCV strains would be advantageous. Our study offers important functional data on how cell culture-adaptive mutations identified in genotype 5a JFH1-based HCVcc permit high-titer culture by affecting HCV genesis through increasing virus assembly and HCV fitness by enhancing the virus specific infectivity and cell-to-cell transmission ability, without influencing the biophysical particle properties. High-titer HCVcc like the one described in this study may be pivotal in future vaccine-related studies where large quantities of infectious HCV particles are necessary.
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Athamneh, Rabaa Y., Ayşe Arıkan, Murat Sayan, Azmi Mahafzah, and Malik Sallam. "Variable Proportions of Phylogenetic Clustering and Low Levels of Antiviral Drug Resistance among the Major HBV Sub-Genotypes in the Middle East and North Africa." Pathogens 10, no. 10 (October 15, 2021): 1333. http://dx.doi.org/10.3390/pathogens10101333.
Full textAbstract:
Hepatitis B virus (HBV) infection remains a major public health threat in the Middle East and North Africa (MENA). Phylogenetic analysis of HBV can be helpful to study the putative transmission links and patterns of inter-country spread of the virus. The objectives of the current study were to analyze the HBV genotype/sub-genotype (SGT) distribution, reverse transcriptase (RT), and surface (S) gene mutations and to investigate the domestic transmission of HBV in the MENA. All HBV molecular sequences collected in the MENA were retrieved from GenBank as of 30 April 2021. Determination of genotypes/SGT, RT, and S mutations were based on the Geno2pheno (hbv) 2.0 online tool. For the most prevalent HBV SGTs, maximum likelihood phylogenetic analysis was conducted to identify the putative phylogenetic clusters, with approximate Shimodaira–Hasegawa-like likelihood ratio test values ≥ 0.90, and genetic distance cut-off values ≤ 0.025 substitutions/site as implemented in Cluster Picker. The total number of HBV sequences used for genotype/SGT determination was 4352 that represented a total of 20 MENA countries, with a majority from Iran (n = 2103, 48.3%), Saudi Arabia (n = 503, 11.6%), Tunisia (n = 395, 9.1%), and Turkey (n = 267, 6.1%). Genotype D dominated infections in the MENA (86.6%), followed by genotype A (4.1%), with SGT D1 as the most common in 14 MENA countries and SGT D7 dominance in the Maghreb. The highest prevalence of antiviral drug resistance was observed against lamivudine (4.5%) and telbivudine (4.3%). The proportion of domestic phylogenetic clustering was the highest for SGT D7 (61.9%), followed by SGT D2 (28.2%) and genotype E (25.7%). The largest fraction of domestic clusters with evidence of inter-country spread within the MENA was seen in SGT D7 (81.3%). Small networks (containing 3-14 sequences) dominated among domestic phylogenetic clusters. Specific patterns of HBV genetic diversity were seen in the MENA with SGT D1 dominance in the Levant, Iran, and Turkey; SGT D7 dominance in the Maghreb; and extensive diversity in Saudi Arabia and Egypt. A low prevalence of lamivudine, telbivudine, and entecavir drug resistance was observed in the region, with almost an absence of resistance to tenofovir and adefovir. Variable proportions of phylogenetic clustering indicated prominent domestic transmission of SGT D7 (particularly in the Maghreb) and relatively high levels of virus mobility in SGT D1.
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Nagasaki, Keizo, Yoko Shirai, Yuji Tomaru, Kensho Nishida, and Shmuel Pietrokovski. "Algal Viruses with Distinct Intraspecies Host Specificities Include Identical Intein Elements." Applied and Environmental Microbiology 71, no. 7 (July 2005): 3599–607. http://dx.doi.org/10.1128/aem.71.7.3599-3607.2005.
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ABSTRACT Heterosigma akashiwo virus (HaV) is a large double-stranded DNA virus infecting the single-cell bloom-forming raphidophyte (golden brown alga) H. akashiwo. A molecular phylogenetic sequence analysis of HaV DNA polymerase showed that it forms a sister group with Phycodnaviridae algal viruses. All 10 examined HaV strains, which had distinct intraspecies host specificities, included an intein (protein intron) in their DNA polymerase genes. The 232-amino-acid inteins differed from each other by no more than a single nucleotide change. All inteins were present at the same conserved position, coding for an active-site motif, which also includes inteins in mimivirus (a very large double-stranded DNA virus of amoebae) and in several archaeal DNA polymerase genes. The HaV intein is closely related to the mimivirus intein, and both are apparently monophyletic to the archaeal inteins. These observations suggest the occurrence of horizontal transfers of inteins between viruses of different families and between archaea and viruses and reveal that viruses might be reservoirs and intermediates in horizontal transmissions of inteins. The homing endonuclease domain of the HaV intein alleles is mostly deleted. The mechanism keeping their sequences basically identical in HaV strains specific for different hosts is yet unknown. One possibility is that rapid and local changes in the HaV genome change its host specificity. This is the first report of inteins found in viruses infecting eukaryotic algae.
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Quer, Josep, Juan Ignacio Esteban, Joan Cos, Sílvia Sauleda, Laura Ocaña, María Martell, Teresa Otero, et al. "Effect of Bottlenecking on Evolution of the Nonstructural Protein 3 Gene of Hepatitis C Virus during Sexually Transmitted Acute Resolving Infection." Journal of Virology 79, no. 24 (December 15, 2005): 15131–41. http://dx.doi.org/10.1128/jvi.79.24.15131-15141.2005.
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ABSTRACT Sexual partners of patients infected with the hepatitis C virus (HCV) often have detectable HCV-specific T-cell responses in the absence of seroconversion, suggesting unapparent, spontaneously resolving infection. To determine whether differences in the evolutionary potential of bottlenecked inoculum may explain the low rate of HCV persistence after sexual exposure, we have investigated changes in the entire HCV nonstructural 3 (NS3) gene over time in a chronic carrier and compared his viral quasispecies with that of the acute-phase isolate of his sexual partner, who developed acute resolving hepatitis C. The overall rate of accumulation of mutations, estimated by regression analysis of six consecutive consensus NS3 sequences over 8 years, was 1.5 × 10−3 mutations per site per year, with small intersample fluctuations related to changes in environmental conditions. Comparison of quasispecies parameters in one isolate of the chronic carrier with those of the acute-phase isolate of the infected partner revealed a higher heterogeneity and lower proportion of nonsynonymous mutations in the former. All NS3 sequences from the acute-phase isolate clustered with a single sequence from the chronic isolate, despite complete HLA mismatch between the patients, suggesting bottlenecking during transmission. The low risk of viral persistence after sexual exposure to HCV may be related to the selection of a limited number of viral particles carrying a particular combination of mutations which may further limit the potential of a relatively homogeneous quasispecies to rapidly diversify and overcome the immune response of the exposed host.
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Shehzad, Sofia. "DENGUE OUTBREAK -IS THE PANIC JUSTIFIED ?" Journal of Gandhara Medical and Dental Science 4, no. 1 (March 20, 2018): 1. http://dx.doi.org/10.37762/jgmds.4-1.224.
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In this era of startling developments in the medical field there remains a serious worry about the hazardous potential of various by products which if not properly addressed can lead to consequences of immense public concern. Hospitals and other health care facilities generate waste products which are evidently hazardous to all those exposed to its potentially harmful effects. Need for effective legislation ensuring its safe disposal is supposed to be an integral part of any country's health related policy. This issue is of special importance in developing countries like Pakistan which in spite of framing various regulations for safeguarding public health, seem to overlook its actual implementation. The result unfortunately is the price wehave to pay not only in terms of rampant spread of crippling infections but a significant spending of health budget on combating epidemics which could easily have been avoided through effective waste disposal measures in the first place. Waste classified under the heading 'bio-hazardous' includes any infectious or potentially infectious material which can be injurious or harmful to humans and other living organisms. Amongst the many potential sources are the hospitals or other health delivery centres which are ironically supposed to be the centres of infection control and treatment. Whilst working in these setups, health care workers such as doctors, nurses, paramedical staff and sanitation workers are actually the ones most exposed and vulnerable to these challenges. Biomedical waste may broadly be classified into Infectious and toxic waste. Infectious waste includes sharps, blood, body fluids and tissues etcwhile substances such as radioactive material and by-products of certain drugs qualify as toxic waste. Furthermore health institutions also have to cater for general municipal waste such as carton boxes, paper and plastics. The World Health Organisation has its own general classification of hospital waste divided into almost eight categories of which almost 15% (10% infectious and 5% toxic) is estimated to be of a hazardous nature while the remaining 85% is general non hazardous content.1A recent study from Faisalabad, Pakistan has estimated hospital waste generation around 1 to 1.5 kg / bed /day for public sector hospitals in the region,2while figures quoted from neighbouring India are approximately 0.5 to 2 KG / hospital bed /day.3 Elsewhere in the world variable daily hospital waste production has been observed ranging from as low as 0.14 to 0.49 kg /day in Korea4 and 0.26 to 0.89 kg/day in Greece5to as high as 2.1 to 3.83 kg/day in Turkey6 and 0.84 to 5.8 kg/day in Tanzania.7Ill effects of improper management of hospital waste can manifest as nosocomial infections or occupational hazards such as needle stick injuries. Pathogens or spores can be borne either through the oro-faecal or respiratory routes in addition to direct inoculation through contact with infected needles or sharps. Environmental pollution can result from improper burning of toxic material leading to emission of dioxins, particulate matter or furans into the air. The habitat can also be affected by illegal dumping and landfills or washing up of medical waste released into the sea or river. Potential organisms implicated in diseases secondary to mismanagement of hospital waste disposal include salmonella, cholera, shigella, helminths, strep pneumonia, measles, tuberculosis, herpesvirus, anthrax, meningitis, HIV, hepatitis and candida etc. These infections can cause a considerable strain on the overall health and finances of the community or individuals affected. The basic principal of Public health management i.e 'prevention is better than cure' cannot be more stressed in this scenario as compared to any other health challenge. Health facilities must have a clear policy on hazardous waste management. To ensure a safe environment hospitals need to adopt and implement international and local systems of waste disposal. Hospital waste management plan entails policy and procedures addressing waste generation, accumulation, handling, transportation, storage, treatment and disposal. Waste needs to be collected in marked containers usually colour coded and leak proof. Segregation at source is of vital importance. The standard practice in many countries is the Basic Three Bin System ie to segregate the waste into RED bags/ boxes for sharps, YELLOW bags for biological waste and BLUE or BLACK ones for general/ municipal waste. All hospital staff needs to be trained in the concept of putting the right waste in relevant containers/ bags. They need to know that more than anything else this practice is vital for their own safety. The message can be reinforced through appropriate labelling on the bins and having posters with simple delineations to avoid mixing of different waste types. Sharps essentially should be kept in rigid, leak and puncture-resistant containers which are tightly lidded and labelled. Regular training sessions for nurses and cleaning staff can be organised as they are the personnel who are more likely to deal with waste disposition at the level of their respective departments. Next of course is transportation of waste products to the storage or disposal. Sanitary staff and janitors must be aware of the basic concepts of waste handling and should wear protective clothing, masks and gloves etc, besides ensuring regular practice of disinfection and sterilization techniques.8Special trolleys or vehicles exclusively designed and reserved for biomedical waste and operated by trained individuals should be used for transportation to the dumping or treatment site. Biomedical waste treatment whether on site or off site is a specialised entity involving use of chemicals and equipment intended for curtailing the hazardous potential of the material at hand. Thermal treatment via incinerators, not only results in combustion of organic substances but the final product in the form of non-toxicash is only 10 to 15% of the original solid mass of waste material fed to the machine. Dedicated autoclaves and microwaves can also be used for the purpose of disinfection. Chemicals such as bleach, sodium hydroxides, chlorine dioxide and sodiumhypochlorite are also effective disinfectants having specialised indications. Countries around the world have their own regulations for waste management. United Kingdom practices strict observance of Environmental protection act 1990, Waste managementlicensing regulations 1994 and Hazardous waste regulations 2005 making it one of thesafest countries in terms of hazardous waste disposal. Similar regulations specific for each state have been adopted in United States following passage of the Medical Waste tracking act 1988. In Pakistan, every hospital must comply with the Waste Management Rules 2005 (Environment Protection Act 1997), though actual compliance is far from satisfactory. It is high time that the government and responsible community organisations shape up to seriously tackle the issue of bio hazardous waste management through enforcement of effective policies and standard operating procedures for safeguarding the health and lives of the public in general and health workers in particular.
Outbreaks, defined as excess cases of a particular disease or illness which outweighs the response capabilities, have the capacity to overwhelm health care facilities and need timely response and attention to details in order to avoid potentially disastrous sequelae . In this day and age when improvement in public health practices have significantly curtailed outbreak of various diseases, certain viral illnesses continue to make headlines. One of the notable vector borne infectious disease affecting significant portions of south east Asia in the early part of twenty first century is 'Dengue fever'. Dreaded as it is by those suffering from the illness, a lot of the hysteria created is secondary to a lack of education and understanding of the nature of the disease and at times a result of disinformation campaign for vested interests by certain political and media sections.'Dengue' in fact is a Spanish word, assumed to have originated from the Swahili phrase -ka dinga peppo -which describes the disease as being caused by evil spirit. 1 Over the course of time it has been called 'breakbone fever', 'bilious vomiting fever', 'break heart fever', 'dandy fever', 'la dengue' and 'Phillipine, Thai and Singapore hemorrhagic fever' Whilst the first reported case referring to dengue fever as a water poison spread by flying insects, exists in the Chinese medical encyclopedia from Jin Dynasty (265-420 AD), the disease is believed to have disseminated from Africa with the spread of the primary vector, aedes egypti, in the 15th to 19th century as a result of globalisation of slave trade 45In 80% of the patients affected by this condition the presentation is rather insidious and at best characterized by mild fever. The classical 'Dengue fever' present in about 5% of the cases is characterized by high temperature, body aches, vomiting and at times a skin rash. The disease may regresses in two to seven days. However inrare instances (<5%) it may develop into more serious conditions such as Dengue hemorrhagic fever whereby the platelet count is significantly reduced leading to bleeding tendencies and may even culminate in a more life threatening presentation i.e Dengue shock syndrome.6To understand the actual dynamics of Dengue epidemic it is important to understand the mode of its spread in affected areas. Aedes mosquito (significantly Aedes Egypti) acts a vector for this disease. Early morning and evening times7 are favoured by these mosquitos to feed on their prey. There is some evidence that the disease may be transmitted via blood products and organ donation. 8 Moreover vertical transmission (mother to child) has also been reported 9Diagnostic investigations include blood antigen detection through NS-I or nucleic acid detection via PCR. IO Cell cultures and specific serology may also be used for confirming the underlying disease. Whilst sporadic and endemic cases are part of routine medical practice and may not raise any alarm bells, outbreaks certainly need mobilization of appropriate resources for effective control. Needless to say 'prevention is better than cure' and should be the primary target of the health authorities in devising strategies for disease control.The WHO recommended 'Integrated Vector control programme', lays stress on social mobilisation and strengthening of public health bodies, coherent response of health and related departments and effective capacity building of relevant personnel and organisations as well as the community at risk. For Aedes Egypti the primary control revolves around eliminating its habitats such as open sources of water. In a local perspective in our city Peshawar, venue of the recent dengue epidemic, it may be seen in the form of incidental reservoirs such as receptacles and tyres dumped in open areas such as roof tops with rain water accumulating in them and provtdjng excellent breeding habitats, Larvicidal and insecticides may be added to more permanent sources such as watertanks and farm lands. There is not much of a role for spraying with organophosphorous agents which is at times resorted to for public consumption. Public education is the key to any effective strategy which must highlight the need for wearing clothing that fully covers the skin, avoiding unnecessary early morning and evening exposure to vector agents, application of insect repellents and use of mosquito nets. It is also important not to panic if affliction with the disease is suspected as in a vast majority of instances it is a self limiting illness without any long term harmful effects and needs simple conservative management like antipyretics and analgesics.An important consideration for responsible authorities in a dengue epidemic is to ensure that maximum management facilities for simple cases are provided at the community level through primary and secondary health care facilities and that the tertiary care hospitals are not inundated with all sort of patients demanding consultation. These later facilities should be reserved for those patients who end up with any complications or more severe manifestation of the disease.Research is underway to develop an ideal vaccine for Dengue fever. In 2016, a vaccine by the name 'Dengvaxia' was marketed in Phillipines and Indonesia. However with development of new serotypes of the virus, its efficacy has been somewhat compromised.As for treatment , there are no specific antiviral drugs. Management is symptomatic revolving mainly around oral and intravenous hydration. Paracetamol (Acetaminophen) is used for fever as compared to NSAIDS such as Ibuprophen infusion as well as blood and platelet transfusion.Data to date shows that slightly more than twenty three thousand people have been diagnosed with dengue over the past three months ie August to October there is a lower risk of bleeding with the former. Those with more severe form of the disease may need Dextran 2017, in Peshawar, Pakistan with around fourteen thousand needing admission and about sixty nine recorded deaths. The mortality is well within the acceptable international standards of less than 1% for the disease. In the backdrop of all the debate surrounding the current epidemic, one can infer that such outbreaks are best addressed with effective planningwell ahead of the time before the disease threatens to spiral out of control. Simple measures such as covering water storage facilities, using larvicidals where practical, use of insect repellents, mosquito nets and avoiding unnecessary exposure can offerthe best protection. Public health messages via print and electronic media can help educate people in affected areas and allay any anxiety building up from a fear of developing life threatening complications. Health department must mobilise all its resources to ensure local management of diagnosed patients with simple dengue fever and facilitate hospital admission only for those suffering from more severe form of the disease. Moreover the media hype into such situations needs to be addressed through constant updates and discouraging any negative politicking on the issue. To sum up Dengue fever is not really an affliction to be dreaded provided it is viewed and managed in the right perspective.
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Shehzad, Sofia. "DENGUE OUTBREAK -IS THE PANIC JUSTIFIED ?" Journal of Gandhara Medical and Dental Science 4, no. 1 (March 20, 2018): 1. http://dx.doi.org/10.37762/jgmds.4-1.224.
Full textAbstract:
In this era of startling developments in the medical field there remains a serious worry about the hazardous potential of various by products which if not properly addressed can lead to consequences of immense public concern. Hospitals and other health care facilities generate waste products which are evidently hazardous to all those exposed to its potentially harmful effects. Need for effective legislation ensuring its safe disposal is supposed to be an integral part of any country's health related policy. This issue is of special importance in developing countries like Pakistan which in spite of framing various regulations for safeguarding public health, seem to overlook its actual implementation. The result unfortunately is the price wehave to pay not only in terms of rampant spread of crippling infections but a significant spending of health budget on combating epidemics which could easily have been avoided through effective waste disposal measures in the first place. Waste classified under the heading 'bio-hazardous' includes any infectious or potentially infectious material which can be injurious or harmful to humans and other living organisms. Amongst the many potential sources are the hospitals or other health delivery centres which are ironically supposed to be the centres of infection control and treatment. Whilst working in these setups, health care workers such as doctors, nurses, paramedical staff and sanitation workers are actually the ones most exposed and vulnerable to these challenges. Biomedical waste may broadly be classified into Infectious and toxic waste. Infectious waste includes sharps, blood, body fluids and tissues etcwhile substances such as radioactive material and by-products of certain drugs qualify as toxic waste. Furthermore health institutions also have to cater for general municipal waste such as carton boxes, paper and plastics. The World Health Organisation has its own general classification of hospital waste divided into almost eight categories of which almost 15% (10% infectious and 5% toxic) is estimated to be of a hazardous nature while the remaining 85% is general non hazardous content.1A recent study from Faisalabad, Pakistan has estimated hospital waste generation around 1 to 1.5 kg / bed /day for public sector hospitals in the region,2while figures quoted from neighbouring India are approximately 0.5 to 2 KG / hospital bed /day.3 Elsewhere in the world variable daily hospital waste production has been observed ranging from as low as 0.14 to 0.49 kg /day in Korea4 and 0.26 to 0.89 kg/day in Greece5to as high as 2.1 to 3.83 kg/day in Turkey6 and 0.84 to 5.8 kg/day in Tanzania.7Ill effects of improper management of hospital waste can manifest as nosocomial infections or occupational hazards such as needle stick injuries. Pathogens or spores can be borne either through the oro-faecal or respiratory routes in addition to direct inoculation through contact with infected needles or sharps. Environmental pollution can result from improper burning of toxic material leading to emission of dioxins, particulate matter or furans into the air. The habitat can also be affected by illegal dumping and landfills or washing up of medical waste released into the sea or river. Potential organisms implicated in diseases secondary to mismanagement of hospital waste disposal include salmonella, cholera, shigella, helminths, strep pneumonia, measles, tuberculosis, herpesvirus, anthrax, meningitis, HIV, hepatitis and candida etc. These infections can cause a considerable strain on the overall health and finances of the community or individuals affected. The basic principal of Public health management i.e 'prevention is better than cure' cannot be more stressed in this scenario as compared to any other health challenge. Health facilities must have a clear policy on hazardous waste management. To ensure a safe environment hospitals need to adopt and implement international and local systems of waste disposal. Hospital waste management plan entails policy and procedures addressing waste generation, accumulation, handling, transportation, storage, treatment and disposal. Waste needs to be collected in marked containers usually colour coded and leak proof. Segregation at source is of vital importance. The standard practice in many countries is the Basic Three Bin System ie to segregate the waste into RED bags/ boxes for sharps, YELLOW bags for biological waste and BLUE or BLACK ones for general/ municipal waste. All hospital staff needs to be trained in the concept of putting the right waste in relevant containers/ bags. They need to know that more than anything else this practice is vital for their own safety. The message can be reinforced through appropriate labelling on the bins and having posters with simple delineations to avoid mixing of different waste types. Sharps essentially should be kept in rigid, leak and puncture-resistant containers which are tightly lidded and labelled. Regular training sessions for nurses and cleaning staff can be organised as they are the personnel who are more likely to deal with waste disposition at the level of their respective departments. Next of course is transportation of waste products to the storage or disposal. Sanitary staff and janitors must be aware of the basic concepts of waste handling and should wear protective clothing, masks and gloves etc, besides ensuring regular practice of disinfection and sterilization techniques.8Special trolleys or vehicles exclusively designed and reserved for biomedical waste and operated by trained individuals should be used for transportation to the dumping or treatment site. Biomedical waste treatment whether on site or off site is a specialised entity involving use of chemicals and equipment intended for curtailing the hazardous potential of the material at hand. Thermal treatment via incinerators, not only results in combustion of organic substances but the final product in the form of non-toxicash is only 10 to 15% of the original solid mass of waste material fed to the machine. Dedicated autoclaves and microwaves can also be used for the purpose of disinfection. Chemicals such as bleach, sodium hydroxides, chlorine dioxide and sodiumhypochlorite are also effective disinfectants having specialised indications. Countries around the world have their own regulations for waste management. United Kingdom practices strict observance of Environmental protection act 1990, Waste managementlicensing regulations 1994 and Hazardous waste regulations 2005 making it one of thesafest countries in terms of hazardous waste disposal. Similar regulations specific for each state have been adopted in United States following passage of the Medical Waste tracking act 1988. In Pakistan, every hospital must comply with the Waste Management Rules 2005 (Environment Protection Act 1997), though actual compliance is far from satisfactory. It is high time that the government and responsible community organisations shape up to seriously tackle the issue of bio hazardous waste management through enforcement of effective policies and standard operating procedures for safeguarding the health and lives of the public in general and health workers in particular.
Outbreaks, defined as excess cases of a particular disease or illness which outweighs the response capabilities, have the capacity to overwhelm health care facilities and need timely response and attention to details in order to avoid potentially disastrous sequelae . In this day and age when improvement in public health practices have significantly curtailed outbreak of various diseases, certain viral illnesses continue to make headlines. One of the notable vector borne infectious disease affecting significant portions of south east Asia in the early part of twenty first century is 'Dengue fever'. Dreaded as it is by those suffering from the illness, a lot of the hysteria created is secondary to a lack of education and understanding of the nature of the disease and at times a result of disinformation campaign for vested interests by certain political and media sections.'Dengue' in fact is a Spanish word, assumed to have originated from the Swahili phrase -ka dinga peppo -which describes the disease as being caused by evil spirit. 1 Over the course of time it has been called 'breakbone fever', 'bilious vomiting fever', 'break heart fever', 'dandy fever', 'la dengue' and 'Phillipine, Thai and Singapore hemorrhagic fever' Whilst the first reported case referring to dengue fever as a water poison spread by flying insects, exists in the Chinese medical encyclopedia from Jin Dynasty (265-420 AD), the disease is believed to have disseminated from Africa with the spread of the primary vector, aedes egypti, in the 15th to 19th century as a result of globalisation of slave trade 45In 80% of the patients affected by this condition the presentation is rather insidious and at best characterized by mild fever. The classical 'Dengue fever' present in about 5% of the cases is characterized by high temperature, body aches, vomiting and at times a skin rash. The disease may regresses in two to seven days. However inrare instances (<5%) it may develop into more serious conditions such as Dengue hemorrhagic fever whereby the platelet count is significantly reduced leading to bleeding tendencies and may even culminate in a more life threatening presentation i.e Dengue shock syndrome.6To understand the actual dynamics of Dengue epidemic it is important to understand the mode of its spread in affected areas. Aedes mosquito (significantly Aedes Egypti) acts a vector for this disease. Early morning and evening times7 are favoured by these mosquitos to feed on their prey. There is some evidence that the disease may be transmitted via blood products and organ donation. 8 Moreover vertical transmission (mother to child) has also been reported 9Diagnostic investigations include blood antigen detection through NS-I or nucleic acid detection via PCR. IO Cell cultures and specific serology may also be used for confirming the underlying disease. Whilst sporadic and endemic cases are part of routine medical practice and may not raise any alarm bells, outbreaks certainly need mobilization of appropriate resources for effective control. Needless to say 'prevention is better than cure' and should be the primary target of the health authorities in devising strategies for disease control.The WHO recommended 'Integrated Vector control programme', lays stress on social mobilisation and strengthening of public health bodies, coherent response of health and related departments and effective capacity building of relevant personnel and organisations as well as the community at risk. For Aedes Egypti the primary control revolves around eliminating its habitats such as open sources of water. In a local perspective in our city Peshawar, venue of the recent dengue epidemic, it may be seen in the form of incidental reservoirs such as receptacles and tyres dumped in open areas such as roof tops with rain water accumulating in them and provtdjng excellent breeding habitats, Larvicidal and insecticides may be added to more permanent sources such as watertanks and farm lands. There is not much of a role for spraying with organophosphorous agents which is at times resorted to for public consumption. Public education is the key to any effective strategy which must highlight the need for wearing clothing that fully covers the skin, avoiding unnecessary early morning and evening exposure to vector agents, application of insect repellents and use of mosquito nets. It is also important not to panic if affliction with the disease is suspected as in a vast majority of instances it is a self limiting illness without any long term harmful effects and needs simple conservative management like antipyretics and analgesics.An important consideration for responsible authorities in a dengue epidemic is to ensure that maximum management facilities for simple cases are provided at the community level through primary and secondary health care facilities and that the tertiary care hospitals are not inundated with all sort of patients demanding consultation. These later facilities should be reserved for those patients who end up with any complications or more severe manifestation of the disease.Research is underway to develop an ideal vaccine for Dengue fever. In 2016, a vaccine by the name 'Dengvaxia' was marketed in Phillipines and Indonesia. However with development of new serotypes of the virus, its efficacy has been somewhat compromised.As for treatment , there are no specific antiviral drugs. Management is symptomatic revolving mainly around oral and intravenous hydration. Paracetamol (Acetaminophen) is used for fever as compared to NSAIDS such as Ibuprophen infusion as well as blood and platelet transfusion.Data to date shows that slightly more than twenty three thousand people have been diagnosed with dengue over the past three months ie August to October there is a lower risk of bleeding with the former. Those with more severe form of the disease may need Dextran 2017, in Peshawar, Pakistan with around fourteen thousand needing admission and about sixty nine recorded deaths. The mortality is well within the acceptable international standards of less than 1% for the disease. In the backdrop of all the debate surrounding the current epidemic, one can infer that such outbreaks are best addressed with effective planningwell ahead of the time before the disease threatens to spiral out of control. Simple measures such as covering water storage facilities, using larvicidals where practical, use of insect repellents, mosquito nets and avoiding unnecessary exposure can offerthe best protection. Public health messages via print and electronic media can help educate people in affected areas and allay any anxiety building up from a fear of developing life threatening complications. Health department must mobilise all its resources to ensure local management of diagnosed patients with simple dengue fever and facilitate hospital admission only for those suffering from more severe form of the disease. Moreover the media hype into such situations needs to be addressed through constant updates and discouraging any negative politicking on the issue. To sum up Dengue fever is not really an affliction to be dreaded provided it is viewed and managed in the right perspective.
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Mutucumarana, Charmaine P., Joshua Eudailey, Erin P. McGuire, Nathan Vandergrift, Gerald Tegha, Charles Chasela, Sascha Ellington, et al. "Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals." Clinical and Vaccine Immunology 24, no. 8 (May 31, 2017). http://dx.doi.org/10.1128/cvi.00062-17.
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ABSTRACT Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers (n = 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.
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Dibble, Kate E., Sarah M. Murray, John Mark Wiginton, Jessica L. Maksut, Carrie E. Lyons, Rohin Aggarwal, Jura L. Augustinavicius, et al. "Associations between HIV testing and multilevel stigmas among gay men and other men who have sex with men in nine urban centers across the United States." BMC Health Services Research 22, no. 1 (September 20, 2022). http://dx.doi.org/10.1186/s12913-022-08572-4.
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Abstract Background Complex manifestation of stigma across personal, community, and structural levels and their effect on HIV outcomes are less understood than effects in isolation. Yet, multilevel approaches that jointly assesses HIV criminalization and personal sexual behavior stigma in relation to HIV testing have not been widely employed or have only focused on specific subpopulations. The current study assesses the association of three types of MSM-related sexual behavior-related stigma (family, healthcare, general social stigma) measured at both individual and site levels and the presence/absence of laws criminalizing HIV transmission with HIV testing behaviors to inform HIV surveillance and prevention efforts among HIV-negative MSM in a holistic and integrated way. Methods We included nine National HIV Behavioral Surveillance (NHBS) 2017 sites: Baltimore, MD; Denver, CO; Detroit, MI; Houston, TX; Long Island/Nassau-Suffolk, NY; Los Angeles, CA; Portland, OR; San Diego, CA; and Virginia Beach and Norfolk, VA. Multivariable generalized hierarchical linear modeling was used to examine how sexual behavior stigmas (stigma from family, anticipated healthcare stigma, general social stigma) measured at the individual and site levels and state HIV criminalization legislation (no, HIV-specific, or sentence-enhancement laws) were associated with past-year HIV testing behaviors across sites (n = 3,278). Results The majority of MSM across sites were tested for HIV in the past two years (n = 2,909, 95.4%) with the average number of times tested ranging from 1.79 (SD = 3.11) in Portland, OR to 4.95 (SD = 4.35) in Los Angeles, CA. In unadjusted models, there was a significant positive relationship between stigma from family and being tested for HIV in the past two years. Site-level HIV-specific criminalization laws were associated with an approximate 5% reduction in the prevalence of receiving any HIV test in the past two years after individual level stigma and sociodemographic covariate adjustments (PR = 0.94, 95% CI, 0.90–0.99). Conclusions Structural barriers faced by MSM persist and ending the HIV epidemic in the US requires a supportive legal environment to ensure effective engagement in HIV services among MSM. Home-based solutions, such as self-testing, used to deliver HIV testing may be particularly important in punitive settings while legal change is advocated for on the community and state levels.
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Quan, Yudong, Hongtao Xu, Yingshan Han, Thibault Mesplède, and Mark A. Wainberg. "JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1." Journal of Virology 91, no. 9 (February 15, 2017). http://dx.doi.org/10.1128/jvi.00075-17.
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ABSTRACT HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-to-cell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses. IMPORTANCE Specific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.
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Fan, Qin, Jiafeng Zhang, Mingyu Luo, Jiaming Yao, Rui Ge, Yong Yan, Xiaobei Ding, Wanjun Chen, and Xiaohong Pan. "Analysis of the Driving Factors of Active and Rapid Growth Clusters Among CRF07_BC-Infected Patients in a Developed Area in Eastern China." Open Forum Infectious Diseases 8, no. 3 (February 4, 2021). http://dx.doi.org/10.1093/ofid/ofab051.
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Abstract Background The purpose of this study was to research the molecular transmission and genetic evolutionary characteristics among CRF07_BC-infected patients in a developed area in Eastern China. Methods Plasma samples from newly diagnosed HIV-1-positive patients from 2015–2018 and basic demographic and epidemiological information were obtained. Pol sequences from CRF07_BC-infected patients were selected for phylogenetic, molecular transmission network, and Bayesian evolutionary analyses. Results Pol sequences were successfully obtained from 258 samples of CRF07_BC. Phylogenetic analysis revealed 2 distinct lineages: lineage 1 (66.3%, 171/258), primarily from men who have sex with men (MSM) and some heterosexual individuals, and lineage 2 (33.7%, 87/258), primarily from heterosexual individuals. Under an optimal genetic distance of 0.01 substitutions/site, 163 individuals (63.2%, 163/258) formed 23 groups comprising 6 clusters and 17 dyads in the networks. A distinctly large and rapidly growing cluster (C1) containing 105 individuals was identified, in which MSM with ≥4 links had quite a high transmission risk (low educational background, active sexual behavior, low sexual protection awareness, etc.). According to Bayesian analyses, most C1 clades formed from 2005 to 2009, most of which were closely geographically related to CRF07_BC epidemic strains from Anhui province. Conclusions Here, we elucidated the local transmission characteristics and epidemic pattern of HIV-1 CRF07_BC, revealing that MSM (especially with ≥4 links) may be a significant driver in the formation of active and rapid growth networks in regional CRF07_BC epidemics. Thus, unique region– and risk group–specific transmission network analysis based on a molecular approach can provide critical and insightful information for more effective intervention strategies to limit future HIV-1 transmission.
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Johnson, Jacklyn, Yinjie Zhai, Hamid Salimi, Nicole Espy, Noah Eichelberger, Orlando DeLeon, Yunxia O'Malley, et al. "Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States." Journal of Virology 91, no. 15 (May 10, 2017). http://dx.doi.org/10.1128/jvi.00174-17.
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ABSTRACT The envelope glycoproteins (Envs) on the surfaces of HIV-1 particles are targeted by host antibodies. Primary HIV-1 isolates demonstrate different global sensitivities to antibody neutralization; tier-1 isolates are sensitive, whereas tier-2 isolates are more resistant. Single-site mutations in Env can convert tier-2 into tier-1-like viruses. We hypothesized that such global change in neutralization sensitivity results from weakening of intramolecular interactions that maintain Env integrity. Three strategies commonly applied to perturb protein structure were tested for their effects on global neutralization sensitivity: exposure to low temperature, Env-activating ligands, and a chaotropic agent. A large panel of diverse tier-2 isolates from clades B and C was analyzed. Incubation at 0°C, which globally weakens hydrophobic interactions, causes gradual and reversible exposure of the coreceptor-binding site. In the cold-induced state, Envs progress at isolate-specific rates to unstable forms that are sensitive to antibody neutralization and then gradually lose function. Agents that mimic the effects of CD4 (CD4Ms) also induce reversible structural changes to states that exhibit isolate-specific stabilities. The chaotropic agent urea (at low concentrations) does not affect the structure or function of native Env. However, urea efficiently perturbs metastable states induced by cold and CD4Ms and increases their sensitivity to antibody neutralization and their inactivation rates Therefore, chemical and physical agents can guide Env from the stable native state to perturbation-sensitive forms and modulate their stability to bestow tier-1-like properties on primary tier-2 strains. These concepts can be applied to enhance the potency of vaccine-elicited antibodies and microbicides at mucosal sites of HIV-1 transmission. IMPORTANCE An effective vaccine to prevent transmission of HIV-1 is a primary goal of the scientific and health care communities. Vaccine-elicited antibodies target the viral envelope glycoproteins (Envs) and can potentially inhibit infection. However, the potency of such antibodies is generally low. Single-site mutations in Env can enhance the global sensitivity of HIV-1 to neutralization by antibodies. We found that such a hypersensitivity phenotype can also be induced by agents that destabilize protein structure. Exposure to 0°C or low concentrations of Env-activating ligands gradually guides Env to metastable forms that expose cryptic epitopes and that are highly sensitive to neutralization. Low concentrations of the chaotropic agent urea do not affect native Env but destabilize perturbed states induced by cold or CD4Ms and increase their neutralization. The concept of enhancing antibody sensitivity by chemical agents that affect the structural stability of proteins can be applied to increase the potency of topical microbicides and vaccine-elicited antibodies.
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Craveur, Pierrick, Anna T. Gres, Karen A. Kirby, Dandan Liu, John A. Hammond, Yisong Deng, Stefano Forli, et al. "Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket." mBio 10, no. 2 (March 12, 2019). http://dx.doi.org/10.1128/mbio.02858-18.
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ABSTRACTHIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy ofin vitroassembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of anN-terminaldomaininterface (NDI) pocket that is amenable to antiviral targeting.IMPORTANCEPrecise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30′ of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.
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Zhao, Bin, Wei Song, Minghui An, Xue Dong, Xin Li, Lu Wang, Jianmin Liu, et al. "Priority Intervention Targets Identified Using an In-Depth Sampling HIV Molecular Network in a Non-Subtype B Epidemics Area." Frontiers in Cellular and Infection Microbiology 11 (March 29, 2021). http://dx.doi.org/10.3389/fcimb.2021.642903.
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Molecular network analysis based on the genetic similarity of HIV-1 is increasingly used to guide targeted interventions. Nevertheless, there is a lack of experience regarding molecular network inferences and targeted interventions in combination with epidemiological information in areas with diverse epidemic strains of HIV-1.We collected 2,173 pol sequences covering 84% of the total newly diagnosed HIV-1 infections in Shenyang city, Northeast China, between 2016 and 2018. Molecular networks were constructed using the optimized genetic distance threshold for main subtypes obtained using sensitivity analysis of plausible threshold ranges. The transmission rates (TR) of each large cluster were assessed using Bayesian analyses. Molecular clusters with the characteristics of ≥5 newly diagnosed cases in 2018, high TR, injection drug users (IDUs), and transmitted drug resistance (TDR) were defined as priority clusters. Several HIV-1 subtypes were identified, with a predominance of CRF01_AE (71.0%, 1,542/2,173), followed by CRF07_BC (18.1%, 393/2,173), subtype B (4.5%, 97/2,173), other subtypes (2.6%, 56/2,173), and unique recombinant forms (3.9%, 85/2,173). The overall optimal genetic distance thresholds for CRF01_AE and CRF07_BC were both 0.007 subs/site. For subtype B, it was 0.013 subs/site. 861 (42.4%) sequences of the top three subtypes formed 239 clusters (size: 2-77 sequences), including eight large clusters (size ≥10 sequences). All the eight large clusters had higher TR (median TR = 52.4/100 person-years) than that of the general HIV infections in Shenyang (10.9/100 person-years). A total of ten clusters including 231 individuals were determined as priority clusters for targeted intervention, including eight large clusters (five clusters with≥5 newly diagnosed cases in 2018, one cluster with IDUs, and two clusters with TDR (K103N, Q58E/V179D), one cluster with≥5 newly diagnosed cases in 2018, and one IDUs cluster. In conclusion, a comprehensive analysis combining in-depth sampling HIV-1 molecular networks construction using subtype-specific optimal genetic distance thresholds, and baseline epidemiological information can help to identify the targets of priority intervention in an area epidemic for non-subtype B.
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Council, Olivia D., Shuntai Zhou, Chase D. McCann, Irving Hoffman, Gerald Tegha, Deborah Kamwendo, Mitch Matoga, Sergei L. Kosakovsky Pond, Myron S. Cohen, and Ronald Swanstrom. "Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without Sexually Transmitted Infection-Associated Urethritis." Journal of Virology 94, no. 12 (April 8, 2020). http://dx.doi.org/10.1128/jvi.00151-20.
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ABSTRACT Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from antiretroviral therapy (ART)-naive men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples, full-length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of proinflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population, indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified, perhaps initially by cellular proliferation but further by limited viral replication. IMPORTANCE HIV-1 infection is a sexually transmitted infection that coexists with other STI. Here, we examined the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.
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Cheeseman, Hannah M., Natalia J. Olejniczak, Paul M. Rogers, Abbey B. Evans, Deborah F. L. King, Paul Ziprin, Hua-Xin Liao, Barton F. Haynes, and Robin J. Shattock. "Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies." Journal of Virology 91, no. 1 (October 19, 2016). http://dx.doi.org/10.1128/jvi.01762-16.
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ABSTRACT Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.
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Lee, Ming Jie, Simon Collins, Daphne Babalis, Nicholas Johnson, Emanuela Falaschetti, A. Toby Prevost, Ambreen Ashraf, et al. "The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection—study protocol for a two-stage randomised phase II trial." Trials 23, no. 1 (April 5, 2022). http://dx.doi.org/10.1186/s13063-022-06151-w.
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Abstract Background Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. Methods RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. Discussion The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. Trial registration The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.