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1
Schmack, Ingo, Seda Ballikaya, Brigitte Erber, Irina Voehringer, Ulrich Burkhardt, Gerd U. Auffarth, and Paul Schnitzler. "Validation of Spiked Postmortem Blood Samples from Cornea Donors on the Abbott ARCHITECT and m2000 Systems for Viral Infections." Transfusion Medicine and Hemotherapy 47, no. 3 (September 24, 2019): 236–43. http://dx.doi.org/10.1159/000502866.
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Background: Transplantation of human corneal tissue is associated with the potential risk of transmittance of viral infections. In accordance with European directives and federal laws, in Germany each tissue donor has to be tested for infectious diseases such as hepatitis B and C virus (HBV and HCV) and human immunodeficiency virus (HIV) infection. However, most of the currently available CE-marked serologic and nucleic acid screening systems are only validated for antemortem blood. Methods: Twenty related and paired ante- and postmortem blood samples from cornea donors were obtained and subsequently analyzed for hepatitis B surface antigen (HBsAg), hepatitis B antibody (anti-HBc), anti-HCV, HCV RNA, anti-HIV-1/2, and HIV p24 Ag using Abbott test systems. The sera were also spiked with reference materials in concentrations giving low and high positivity for HBV, HCV, and HIV markers. Results: The spiked ante- and postmortem sera from related donors showed similar results for HBsAg, anti-HBc, anti-HCV, HCV RNA, anti-HIV, and HIV p24 Ag, indicating a high stability of viral markers in cadaveric specimens. Three cornea donors had a medical history of HBV infection and revealed anti-HBc at similar levels in the ante- and postmortem sera. In addition, there was a single postmortem sample demonstrating a weak signal of anti-HIV-1 and HIV-1 p24 Ag. False-positive or false-negative results were not detected. The results obtained with the Abbott ARCHITECT analyzer and Abbott RealTime HCV PCR showed no significant differences. Conclusion: The analyzed screening assays are suitable for the detection of infectious markers of HBV, HCV, and HIV at similar levels in spiked ante- and postmortem sera from cornea donors.
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Miller, M. D., M. T. Warmerdam, I. Gaston, W. C. Greene, and M. B. Feinberg. "The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages." Journal of Experimental Medicine 179, no. 1 (January 1, 1994): 101–13. http://dx.doi.org/10.1084/jem.179.1.101.
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Considerable controversy and uncertainty have surrounded the biological function of the Human Immunodeficiency Virus (HIV)-1 nef gene product. Initial studies suggested that this early, nonstructural viral protein functioned as a negative regulatory factor; thus, it was proposed to play a role in establishing or maintaining viral latency. In contrast, studies in Simian Immunodeficiency Virus (SIV)mac-infected rhesus monkeys have suggested that Nef is not a negative factor but rather plays a central role in promoting high-level viral replication and is required for viral pathogenesis in vivo. We sought to define a tissue culture system that would approximate the in vivo setting for virus infection in order to assess the role of HIV-1 Nef in viral replication. We show that infection of mitogen-activated peripheral blood mononuclear cells (PBMC) with Nef+ HIV results in enhanced replication as evidenced by earlier gag p24 expression when compared with infections performed with nef mutant viruses. Moreover, when unstimulated freshly isolated PBMC are infected with Nef+ and Nef- viruses and then subsequently activated with mitogen, the Nef-induced difference in viral replication kinetics is even more pronounced, with the Nef- viruses requiring much more time in culture for appreciable growth. A positive effect of Nef on viral replication was also observed in primary macrophages infected with a recombinant of YU-2, a patient-derived molecular clone with macrophage tropism. These positive effects of Nef on viral replication are dependent on the initial multiplicity of infection (MOI), in that infections of unstimulated PBMC at low MOI are most dependent upon intact nef for subsequent viral growth. We now provide evidence that the Nef+ HIV is more infectious than Nef- HIV from both a tissue culture infectious dose analysis, and a single-cell HIV infection assay. In the latter case, we demonstrate that infection with equivalent doses of HIV based on virion-associated gag p24 yields five- to sixfold more infected cells if Nef+ viral stocks were used. Furthermore, we find that the differential infectivity is not dependent on CD4 down-regulation as Nef+ virus produced from transfected COS cells lacking CD4 is also more infectious. However, normalization of PBMC infections to equivalent infectivity between that of the Nef+ and Nef- viruses continues to reveal delayed viral replication in the absence of Nef, suggesting that secondary viral spread in PBMC is also enhanced in Nef+ infections. We demonstrate this directly by showing a 13-15-fold increase in infectivity of PBMC-derived Nef+ HIC.(ABSTRACT TRUNCATED AT 400 WORDS)
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Swiecki, Melissa, Yaming Wang, William Vermi, Susan Gilfillan, Robert D. Schreiber, and Marco Colonna. "Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo." Journal of Experimental Medicine 208, no. 12 (November 14, 2011): 2367–74. http://dx.doi.org/10.1084/jem.20110654.
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Plasmacytoid dendritic cells (pDCs) specialize in the secretion of type I interferons (IFN-I) and thus are considered critical mediators of antiviral responses. We recently reported that pDCs have a very early but limited and transient capacity to curtail viral infections. Additionally, pDC numbers are not sustained in human infections caused by Hepatitis B or C viruses (HBV and HCV) and HIV. Thus, the numbers and/or function of pDCs appear to be regulated during the course of viral infection. In this study, we show that splenic pDCs are reduced in vivo during several systemic viral infections and after administration of synthetic toll-like receptor ligands. We demonstrate that IFN-I, regardless of the source, contributes to this decline and mediates pDC death via the intrinsic apoptosis pathway. These findings demonstrate a feedback control mechanism by which IFN-I modulates pDC numbers, thus fine-tuning systemic IFN-I response to viruses. IFN-I–mediated control of pDCs may explain the loss of pDCs during human infections caused by HBV, HCV, or HIV and has important therapeutic implications for settings in which IFN-I is used to treat infections and autoimmune diseases.
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Yokozaki, Shouichi, Junki Takamatsu, Isao Nakano, Yoshiaki Katano, Hidenori Toyoda, Kazuhiko Hayashi, Tetsuo Hayakawa, and Yoshihide Fukuda. "Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy." Blood 96, no. 13 (December 15, 2000): 4293–99. http://dx.doi.org/10.1182/blood.v96.13.4293.
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Abstract Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or both is common in hemophiliac patients due to putative transmission through clotting factor concentrates. Recently, highly active antiretroviral therapy (HAART) has been found to markedly improve viremia and immunologic parameters in patients infected with HIV. This report considers interactions between these viral infections, the immune system, and antiretroviral therapy. A total of 130 male hemophiliac patients were grouped according to type of viremia (HCV, HIV, both, or neither). Along with 30 healthy men age-matched to viremic patients, these groups were compared with respect to viral load and immunologic parameters. Thirty-five patients treated as above for HIV were serially followed up. HCV infection was associated with reduced peripheral B-cell and CD4+-cell counts and with increased serum IgG and IgM levels, whereas HIV infection was associated with reduced peripheral CD4+-cell counts and increased serum IgG and IgA levels. In patients with both viruses, HCV and HIV RNA load correlated inversely with peripheral B-cell and CD4+-cell counts, respectively. HAART reduced levels of both viruses in the blood. Of the 25 patients with both viruses, HAART eliminated HCV in 2. In conclusion, immunologic dynamics differed between hemophiliac patients infected with HCV, HIV, or both. The relative dynamics of HCV viral load, peripheral B-cell count, and serum IgM level were similar to those of HIV viral load, CD4+-cell count, and serum IgA.
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Yokozaki, Shouichi, Junki Takamatsu, Isao Nakano, Yoshiaki Katano, Hidenori Toyoda, Kazuhiko Hayashi, Tetsuo Hayakawa, and Yoshihide Fukuda. "Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy." Blood 96, no. 13 (December 15, 2000): 4293–99. http://dx.doi.org/10.1182/blood.v96.13.4293.h8004293_4293_4299.
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Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or both is common in hemophiliac patients due to putative transmission through clotting factor concentrates. Recently, highly active antiretroviral therapy (HAART) has been found to markedly improve viremia and immunologic parameters in patients infected with HIV. This report considers interactions between these viral infections, the immune system, and antiretroviral therapy. A total of 130 male hemophiliac patients were grouped according to type of viremia (HCV, HIV, both, or neither). Along with 30 healthy men age-matched to viremic patients, these groups were compared with respect to viral load and immunologic parameters. Thirty-five patients treated as above for HIV were serially followed up. HCV infection was associated with reduced peripheral B-cell and CD4+-cell counts and with increased serum IgG and IgM levels, whereas HIV infection was associated with reduced peripheral CD4+-cell counts and increased serum IgG and IgA levels. In patients with both viruses, HCV and HIV RNA load correlated inversely with peripheral B-cell and CD4+-cell counts, respectively. HAART reduced levels of both viruses in the blood. Of the 25 patients with both viruses, HAART eliminated HCV in 2. In conclusion, immunologic dynamics differed between hemophiliac patients infected with HCV, HIV, or both. The relative dynamics of HCV viral load, peripheral B-cell count, and serum IgM level were similar to those of HIV viral load, CD4+-cell count, and serum IgA.
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Troisi, CL, FB Hollinger, WK Hoots, C. Contant, J. Gill, M. Ragni, R. Parmley, C. Sexauer, E. Gomperts, and G. Buchanan. "A multicenter study of viral hepatitis in a United States hemophilic population." Blood 81, no. 2 (January 15, 1993): 412–18. http://dx.doi.org/10.1182/blood.v81.2.412.412.
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Abstract Hemophilia A and B patients seen at nine US regional treatment centers were tested for serologic markers of hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) during 1987 and 1988. Because human immunodeficiency virus (HIV) infection, a potentially confounding variable, was present in 53% of the group, the population was divided by HIV status for analysis purposes. In the HIV-positive group (N = 382), less than 1% had not been infected with HBV, HCV, or HDV, whereas 75% had evidence of infection with HBV and 98% with HCV. HBsAg, a marker of active HBV infection, was present in 12% of subjects; 96% of these were HCV positive. Anti-HDV was detected in 35 subjects (9.1%); all were anti-HBc positive. Ten of the 35 (29%) also were positive for IgM anti-HDV, indicating current infection. All 10 were HBsAg positive and 7 of the 9 tested were HDV RNA positive. Severe/moderate hemophilia B patients were more likely to have experienced an HBV infection and to be anti-HDV positive than were similar hemophilia A patients (22% v 8%, P < .05). In the HIV-negative group (N = 345), the subjects were younger and had less severe hemophilia than the HIV-positive patients. No evidence of HBV, HCV, or HDV infection was found in 18%, whereas 33% had experienced HBV infection and 79% were anti-HCV positive. Within this group, 4% were HBsAg positive. All 13 subjects with anti-HDV (4% of the HIV-negative group) also possessed anti-HBc. One (7.7%) was IgM anti-HDV positive and the serum from another contained HDV RNA. Both of these individuals were HBsAg positive. As in the HIV-positive group, severe/moderate hemophilia B patients were more likely to be HBV and HDV positive than were hemophilia A patients (9% v 3%, P < .05). A prevalence study of viral hepatitis in a large US hemophilic population showed that active infection with HCV is common, occurring in 89% of all study patients regardless of HIV status. Evidence of active HBV infection was found in 8%; 19% of these were actively infected with HDV. HDV was more common in hemophilia B patients after controlling for disease severity.
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Troisi, CL, FB Hollinger, WK Hoots, C. Contant, J. Gill, M. Ragni, R. Parmley, C. Sexauer, E. Gomperts, and G. Buchanan. "A multicenter study of viral hepatitis in a United States hemophilic population." Blood 81, no. 2 (January 15, 1993): 412–18. http://dx.doi.org/10.1182/blood.v81.2.412.bloodjournal812412.
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Hemophilia A and B patients seen at nine US regional treatment centers were tested for serologic markers of hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) during 1987 and 1988. Because human immunodeficiency virus (HIV) infection, a potentially confounding variable, was present in 53% of the group, the population was divided by HIV status for analysis purposes. In the HIV-positive group (N = 382), less than 1% had not been infected with HBV, HCV, or HDV, whereas 75% had evidence of infection with HBV and 98% with HCV. HBsAg, a marker of active HBV infection, was present in 12% of subjects; 96% of these were HCV positive. Anti-HDV was detected in 35 subjects (9.1%); all were anti-HBc positive. Ten of the 35 (29%) also were positive for IgM anti-HDV, indicating current infection. All 10 were HBsAg positive and 7 of the 9 tested were HDV RNA positive. Severe/moderate hemophilia B patients were more likely to have experienced an HBV infection and to be anti-HDV positive than were similar hemophilia A patients (22% v 8%, P < .05). In the HIV-negative group (N = 345), the subjects were younger and had less severe hemophilia than the HIV-positive patients. No evidence of HBV, HCV, or HDV infection was found in 18%, whereas 33% had experienced HBV infection and 79% were anti-HCV positive. Within this group, 4% were HBsAg positive. All 13 subjects with anti-HDV (4% of the HIV-negative group) also possessed anti-HBc. One (7.7%) was IgM anti-HDV positive and the serum from another contained HDV RNA. Both of these individuals were HBsAg positive. As in the HIV-positive group, severe/moderate hemophilia B patients were more likely to be HBV and HDV positive than were hemophilia A patients (9% v 3%, P < .05). A prevalence study of viral hepatitis in a large US hemophilic population showed that active infection with HCV is common, occurring in 89% of all study patients regardless of HIV status. Evidence of active HBV infection was found in 8%; 19% of these were actively infected with HDV. HDV was more common in hemophilia B patients after controlling for disease severity.
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Goulder, Philip J. R., Marcus A. Altfeld, Eric S. Rosenberg, Thi Nguyen, Yanhua Tang, Robert L. Eldridge, Marylyn M. Addo, et al. "Substantial Differences in Specificity of HIV-Specific Cytotoxic T Cells in Acute and Chronic HIV Infection." Journal of Experimental Medicine 193, no. 2 (January 8, 2001): 181–94. http://dx.doi.org/10.1084/jem.193.2.181.
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Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201–restricted CTL response is directed towards the epitope SLYNTVATL (“SL9”) in p17 Gag (residues 77–85). This epitope is targeted by 75% of HLA-A*0201–positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide–major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201–positive subjects with acute HIV-1 infection (P = 2 × 10−6), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201–positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.
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Ong, Catherine Wei Min, Giovanni Battista Migliori, Mario Raviglione, Gavin MacGregor-Skinner, Giovanni Sotgiu, Jan-Willem Alffenaar, Simon Tiberi, et al. "Epidemic and pandemic viral infections: impact on tuberculosis and the lung." European Respiratory Journal 56, no. 4 (June 25, 2020): 2001727. http://dx.doi.org/10.1183/13993003.01727-2020.
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Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.
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Manapova, E. R., V. Kh Fazylov, and A. T. Beshimov. "Clinical and immunological characteristic of natural course at the early stages of HIV infection." Medical Immunology (Russia) 22, no. 3 (May 21, 2020): 519–26. http://dx.doi.org/10.15789/1563-0625-cai-1866.
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An early-stage infection induces the most powerful reactions of immune system. 137 clinical histories of patients with HIV infection, and HCV/HIV-infected at the early stages of HIV infection were subjected to analysis. Patients and methods: a group of 45 patients at early terms of HIV infection included 25 cases of HCV/HIV-infected patients (first group), and 20 cases with HIV mono-infection (second group). Duration of infection was less than 1 year (with positive ELISA test), with mean terms of HIV immunoblot positivity of 5.5±0.6 months. For comparative analysis, the natural course group was examined, i.e., 43 patients with combined HCV/HIV infection (third group), and 49, with HIV monoinfection (fourth group) with a duration of HIV infection for 4.4±0.21 years. The group of healthy controls included 52 persons. We aimed to perform a comparative evaluation of clinical course and immunological features from the early stages of infection in the patients with combined HCV/HIV and HIV infection. Results: at early stages of infection, clinical pattern in HCV/HIV-infected patients was dominated by purulent-inflammatory, fungal infections and secondary diseases, along with more pronounced inhibition of cellular immunity and increased viral load of RNA HIV, as compared to data on HIV-infected patients.
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Aljehawi, Nabil A., Omran O. Bugrein, Azza Grew, and Gamal Ahmed Duweb. "Cutaneous Manifestations in HIV Infected Libyan Patients." Serbian Journal of Dermatology and Venereology 9, no. 3 (September 1, 2017): 113–18. http://dx.doi.org/10.1515/sjdv-2017-0011.
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Abstract Cutaneous manifestations of human immunodeficiency virus (HIV) disease may result from HIV infection itself, or from opportunistic disorders secondary to the declined immunocompetence due to the disease. A total of 220 HIV positive patients, treated in the Benghazi Center of Infectious Diseases and Immunology over a period of 14 years (January 2003 to November 2016), were included in a retrospective study. The patients' age ranged from 7 to 46 years. The study was conducted by reviewing the patients' records using the management information system (MIS). Statistical analysis of the data was carried out by the t-test and Chi square test. Among the studied patients, 119 (54.1%) were males and 101 (45.9%) were females, and most of them (78.6%) were 10 – 19 years of age. The predominant mode of transmission was parenteral transmission, in 95% of patients, and positive family history was observed in 12% of patients. Among the total number of visits to dermatologists, 93% of patients had a single disease. Of the total number of skin diseases diagnosed during the visits, parasitic infestations were seen in 92 patients (21.0%), eczematous and related disorders in 78 patients (17.8%), viral infections in 71 patients (16.2%), bacterial infections in 41 patients (9.3%), and fungal infections in 35 patients (7.9%). Dermatophyte infections were the most common fungal infections recorded in 19 patients (4.3%), followed by Candida infection in 11 patients (2.5%). Warts were found in 5.9% of viral infections, followed by herpes zoster (4.1%). HIV positive patients should be examined for skin disorders, because early diagnosis and management of such problems improves the quality of life in these patients.
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Sung, C. C., J. S. Boomer, T. S. Givens, B. K. DuChateau, M. R. Lepe, A. Feller, M. P. Westerman, A. Gilman-Sachs, A. Chedid, and K. D. Beaman. "Expression of Regeneration and Tolerance Factor Correlates Directly with Human Immunodeficiency Virus Infection and Inversely with Hepatitis C Virus Infection." Clinical Diagnostic Laboratory Immunology 7, no. 2 (March 1, 2000): 200–205. http://dx.doi.org/10.1128/cdli.7.2.200-205.2000.
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ABSTRACT Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause two of the most prevalent debilitating viral infections. HIV appears to induce a skewing toward a Th2 response, while in HCV infection a Th1 response appears to dominate. Regeneration and tolerance factor (RTF) may participate in driving or sustaining a Th2 cytokine response. The expression of RTF on CD3+ T cells of HIV-seropositive (HIV+) individuals is increased. The purpose of this study was to compare the expression of RTF during HIV infections with that during HCV infections. Three-color flow-cytometric analysis of peripheral blood collected from HIV+HCV-seropositive (HCV+), HIV- and HCV-seropositive (HIV+ HCV+), and HIV- and HCV-seronegative (HIV− HCV−) individuals was performed. Levels of RTF expression on T-lymphocyte subsets from these groups were compared, as were levels of RTF expression on activated T cells expressing CD38 and HLA-DR, to determine the relationship of RTF expression to these infections. We demonstrated that the expression of RTF on surfaces of T cells from HIV+ individuals is upregulated and that its expression on T cells from HCV+individuals is downregulated. A twofold increase in the mean channel fluorescence of RTF on CD3+ T cells was seen in both HIV+ and HIV+ HCV+ individuals compared to HIV− HCV− individuals. HCV+ individuals had lower levels of RTF expression than HIV− HCV− individuals (P < 0.005 for CD4+; P < 0.0005 for CD8+). In terms of percentages of T cells expressing RTF, the groups were ranked as follows: HIV+ > HIV+ HCV+ > HIV−HCV− > HCV+. The results indicate that RTF expression correlates with HIV-associated immune activation and may be associated with Th2-type responses.
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Hafler, David A., and Vijay Kuchroo. "TIMs: central regulators of immune responses." Journal of Experimental Medicine 205, no. 12 (November 17, 2008): 2699–701. http://dx.doi.org/10.1084/jem.20082429.
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Exhaustion of T cell responses during chronic viral infections has been observed in both mouse and man and has been attributed to up-regulation of PD-1 on the surface of exhausted T cells. In patients with chronic human HIV infection, T cell exhaustion leads to opportunistic infections associated with AIDS. However, not all the exhausted T cells express PD-1, suggesting that other molecules may be involved in the phenotype. A new study now demonstrates a central role for T cell immunoglobulin and mucin domain–containing protein-3 (TIM-3) in T cell exhaustion during chronic HIV infection and suggests that TIM-3 may be a novel therapeutic target in chronic viral diseases.
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Lauer, Georg M., Tam N. Nguyen, Cheryl L. Day, Gregory K. Robbins, Theresa Flynn, Katherine McGowan, Eric S. Rosenberg, et al. "Human Immunodeficiency Virus Type 1-Hepatitis C Virus Coinfection: Intraindividual Comparison of Cellular Immune Responses against Two Persistent Viruses." Journal of Virology 76, no. 6 (March 15, 2002): 2817–26. http://dx.doi.org/10.1128/jvi.76.6.2817-2826.2002.
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ABSTRACT Both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) lead to chronic infection in a high percentage of persons, and an expanding epidemic of HIV-1-HCV coinfection has recently been identified. These individuals provide an opportunity for simultaneous assessment of immune responses to two viral infections associated with chronic plasma viremia. In this study we analyzed the breadth and magnitude of the CD8+- and CD4+-T-lymphocyte responses in 22 individuals infected with both HIV-1 and HCV. A CD8+-T-lymphocyte response against HIV-1 was readily detected in all subjects over a broad range of viral loads. In marked contrast, HCV-specific CD8+-T-lymphocyte responses were rarely detected, despite viral loads in plasma that were on average 1,000-fold higher. The few HCV-specific responses that were observed were relatively weak and limited in breadth. CD4-proliferative responses against HIV-1 were detected in about half of the coinfected subjects tested, but no proliferative response against any HCV protein was found in these coinfected persons. These data demonstrate a major discordance in immune responses to two persistent RNA viruses. In addition, they show a consistent and profound impairment in cellular immune responses to HCV compared to HIV-1 in HIV-1-HCV-coinfected persons.
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Ndifontiayong, Adamu Ndongho, Innocent Mbulli Ali, Jean Baptiste Sokoudjou, Jerimiah Mbogwe Ndimumeh, and Christopher Bonglavnyuy Tume. "The Effect of HBV/HCV in Response to HAART in HIV Patients after 12 Months in Kumba Health District in the South West Region of Cameroon." Tropical Medicine and Infectious Disease 6, no. 3 (August 10, 2021): 150. http://dx.doi.org/10.3390/tropicalmed6030150.
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Hepatitis B (HBV) and C (HCV) are two among the numerous forms of infections whose clinical degeneration, morbidity–mortality and low immune responsiveness in people living with human immunodeficiency virus (HIV) are highly evident. Co-infection of HIV with HBV and HCV has been associated with reduced survival, increased risk of progression to liver diseases and increased risk of hepatotoxicity associated with antiretroviral therapy (ARV). We carried out biochemical, immunological, virological and clinical analysis of hepatitis B and C positive HIV patients as well as some HIV positive individuals receiving antiretroviral therapy in Kumba Health District to evaluate the immune response to the ARV therapy and identified risk factors associated with the treatment outcomes. A total of 52 HIV patients, 36 HIV/HBV and 12 HIV/HCV patients were involved in this study. We performed CD4 counts, viral load test, analyzed ALAT/ASAT, albumin, bilirubin, and creatinine and measured the weights of HIV patients, HIV/HBV and HIV/HCV enrolled for not more than one year in Kumba Health District. The results were analyzed to evaluate the immune response and possible risk factors associated with the treatment outcomes. The mean increase in weight in participants of all groups over 12 months (17.12 kg) was greater than the mean increase in CD4 (8.92 cell/mm3). However, the mean decrease in viral loads over a 12 months was also very high (1035.17 copies/mL). There was a significant change in the mean values from baseline for all the three variables (p < 0.0001). HIV disease outcomes following HAART (high active antiretroviral therapy) do not appear to be adversely affected by HBV or HCV co-infection, except for slightly poorer CD4 count responses in HIV/HCV co-infected patients. Concerning the renal and liver functions, all the biomarkers witnessed a decrease in patients of all groups in response to HAART over time, with a more rapid decrease in mono-infected patients as compared with those co-infected with HBV but the case was contrary for those co-infected with HCV. Co-infection with HBV or HCV was relatively common among HIV infected participants in Kumba Health District. There were differences in response to HAART between the mono-infected compared with the co-infected, taking into consideration the weight, CD4 count, and viral load. In addition, there was also a variation in the different biomarkers of liver and renal function between mono-infected and co-infected patients.
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Stacey, Andrea R., Philip J. Norris, Li Qin, Elizabeth A. Haygreen, Elizabeth Taylor, John Heitman, Mila Lebedeva, et al. "Induction of a Striking Systemic Cytokine Cascade prior to Peak Viremia in Acute Human Immunodeficiency Virus Type 1 Infection, in Contrast to More Modest and Delayed Responses in Acute Hepatitis B and C Virus Infections." Journal of Virology 83, no. 8 (January 28, 2009): 3719–33. http://dx.doi.org/10.1128/jvi.01844-08.
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ABSTRACT Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1) infection is of critical importance for an understanding of early viral pathogenesis and prophylactic vaccine design. Here, we used sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV-1 (or, for comparison, hepatitis B virus [HBV]or hepatitis C virus [HCV]) to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. Plasma viremia was quantitated over time, and levels of 30 cytokines and chemokines were measured using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. The increase in plasma viremia in acute HIV-1 infection was found to be associated with elevations in plasma levels of multiple cytokines and chemokines, including rapid and transient elevations in alpha interferon (IFN-α) and interleukin-15 (IL-15) levels; a large increase in inducible protein 10 (IP-10) levels; rapid and more-sustained increases in tumor necrosis factor alpha and monocyte chemotactic protein 1 levels; more slowly initiated elevations in levels of additional proinflammatory factors including IL-6, IL-8, IL-18, and IFN-γ; and a late-peaking increase in levels of the immunoregulatory cytokine IL-10. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection and a delayed response of more intermediate magnitude in acute HCV infection, indicating that the rapid activation of a striking systemic cytokine cascade is not a prerequisite for viral clearance (which occurs in a majority of HBV-infected individuals). The intense early cytokine storm in acute HIV-1 infection may have immunopathological consequences, promoting immune activation, viral replication, and CD4+ T-cell loss.
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Sehgal, Mohit, Zafar K. Khan, Andrew H. Talal, and Pooja Jain. "Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle?" Virology: Research and Treatment 4 (January 2013): VRT.S11046. http://dx.doi.org/10.4137/vrt.s11046.
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Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Churruca, Juan, Mariana Bastos-Oreiro, Julia Suárez González, Carolina Martinez-Laperche, Pascual Balsalobre, Pilar Miralles, Juan Berenguer, et al. "Infectious Complications and Mortality after Autologous Stem Cell Transplantation for Lymphomas: A Comparison Between HIV-Infected and HIV-Negative Patients." Blood 128, no. 22 (December 2, 2016): 2258. http://dx.doi.org/10.1182/blood.v128.22.2258.2258.
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Abstract Introduction: Lymphomas continue to be a leading cause of death in HIV-positive patients (HIV+ pts) in the cART era. The aim of this study was to review our 15-year single institution experience in performing Autologous Stem Cell Transplantation (ASCT) for HIV-infected and non-HIV patients with high-risk or relapsed lymphomas, focusing on infectious complications. Patients and Methods: We retrospectively evaluated our cohort of 28 HIV+ pts who underwent an ASCT between 2000-2015, and compared it with a well-matched control group of 39 HIV-negative pts. Patient and ASCT characteristics are described in Table 1. All HIV+ pts were on cART. Chemomobilization was used in 60% of the HIV cohort and 84% of the controls. BEAM conditioning regimen was the most common. All transplants were performed in the same tertiary hospital JACIE-accredited SCT unit. The primary end points were first-year cumulative incidence (CI) of infection, total infectious episodes and infection-related mortality. For the analysis, we defined 3 different time frames: 1st Pre-engraftment; 2nd from engraftment to day +100 and 3rd from day +100 until 1 year after SCT. Events occurring during the first 2 periods were considered early infections as compared to late. Results: All patients received antiviral and anti-PJP prophylaxis, but a significantly higher proportion of HIV+ pts were given antibacterial and antifungal prophylaxis (2/3 vs 1/3 approximately, Table 1). G-CSF support was initiated in all HIV recipients and 66% of controls, and the median days of use was longer for the HIV group (7 vs 4 days, p= 0.04). Median time to neutrophil engraftment was similar in both groups (13 vs 11 days, p=0.55); 93% of HIV pts and all control pts reached ANC > 500c/uL by day +30. Infectious episodes (IE) are described in Table 2, divided by pathogen subtype and time frame. Globally, all infection subtypes were more common in the HIV-infected cohort at some point. The most significant findings from the analysis are as follows. CI of early global infections: HIV 75% vs non-HIV 25% (p= 0.04), Figure 1. Median number of global infectious events: HIV 65 vs non-HIV 39 (p= 0.002; OR 1.8 [1.2-2.8]). Bacteria: CI of pre-engraftment and early bacterial infections were not different among groups (42% vs 28%, p= 0.47), but the median number of bacterial episodes was clearly different: HIV 17 vs non-HIV 12 (p= 0.08; OR 2.16 [0.96-4.8]). Fungi: CI of early fungal infections: HIV 10.7% vs non-HIV 0% (p= 0.03); minor infections were not considered. Viruses: CI of early viral infections: HIV 46% vs non-HIV 15% (p= 0.004). Median nº of early viral IE: HIV 19 vs non-HIV 6 (p= 0.007; OR 4.16 [1.43-12]). CI of late viral infections: HIV 30% vs non-HIV 11.7% (p= 0.04). CMV reactivations were by far more common in the HIV cohort (p=0,01). HIV viral load bleeps were documented in 35% of the HIV patients (most commonly in the day +30 control) and one post-transplant virological failure was diagnosed, forcing HAART substitution. Of note, 1st year CI of infection-related mortality was 14% in the HIV group vs 0% in the non-HIV group (p= 0.01), Figure 2. Three HIV+ pts suffered early fulminant septic episodes (1 E. coli + Enterococcus, 1 Rothiamucilaginosa, 1 non-clarified - possible Stenotrophomonasmaltophilia) and a 29-year old woman in CR after a 1st line for a stage IVsB Burkitt-like lymphoma died due to a severe influenza A pneumonia. Length of admission was also significantly longer for the HIV+ pts (median days 34 vs 28, p=0.041). Regarding long-term outcome, median follow up as of July 2016 is 82 months for the HIV+ group and 70 months for the control group: 57% and 61% of the pts in each cohort are still alive, respectively. One HIV-infected pt and 3 controls have been lost to follow-up. EFS: 1 year 71.4% vs 81.9% (ns); 5 years: 63.9% vs 66.5% (ns). Overall Survival: 1 year 75% vs 84% (ns); 5 years 66.3% vs 74.6% (ns). Conclusion: Autologous stem cell transplantation has been proven to be feasible and effective in HIV-related lymphomas, but in our experience and despite great advances in cART and virological control, HIV+ patients are at high risk of infection and this might influence post-ASCT short-term survival. It is mandatory to focus on prophylactic and supportive measures and to choose carefully the optimal timing for transplantation. Table 2 Table 2. Disclosures No relevant conflicts of interest to declare.
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Bullington, Brooke W., Katherine Klemperer, Keith Mages, Andrea Chalem, Humphrey D. Mazigo, John Changalucha, Saidi Kapiga, Peter F. Wright, Maria M. Yazdanbakhsh, and Jennifer A. Downs. "Effects of schistosomes on host anti-viral immune response and the acquisition, virulence, and prevention of viral infections: A systematic review." PLOS Pathogens 17, no. 5 (May 20, 2021): e1009555. http://dx.doi.org/10.1371/journal.ppat.1009555.
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Although a growing number of studies suggest interactions between Schistosoma parasites and viral infections, the effects of schistosome infections on the host response to viruses have not been evaluated comprehensively. In this systematic review, we investigated how schistosomes impact incidence, virulence, and prevention of viral infections in humans and animals. We also evaluated immune effects of schistosomes in those coinfected with viruses. We screened 4,730 studies and included 103. Schistosomes may increase susceptibility to some viruses, including HIV and Kaposi’s sarcoma-associated herpesvirus, and virulence of hepatitis B and C viruses. In contrast, schistosome infection may be protective in chronic HIV, Human T-cell Lymphotropic Virus-Type 1, and respiratory viruses, though further research is needed. Schistosome infections were consistently reported to impair immune responses to hepatitis B and possibly measles vaccines. Understanding the interplay between schistosomes and viruses has ramifications for anti-viral vaccination strategies and global control of viral infections.
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Setiabudi, Djatnika, Citra Cesilia, Almira Aliyannissa, and Heda Melinda Nataprawira. "Virologic and immunologic status of children with HIV-TB co-infections." Paediatrica Indonesiana 61, no. 2 (March 16, 2021): 94–9. http://dx.doi.org/10.14238/pi61.2.2021.94-9.
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Background Studies about virologic and immunologic status of HIV children are lacking. Tuberculosis (TB) is the most common opportunistic infection in HIV patients and co-infection is associated with much worse prognosis.
Objective To describe the virologic and immunologic status of patients with HIV and TB co-infection, before and after HIV and TB treatment.
Methods A prospective study was conducted in HIV co-infected with TB patients in an Indonesian tertiary hospital between November 2016—December 2018. Viral load and CD4 levels were performed at diagnosis and after 6 months of HIV and TB treatment.
Results Of 44 children hospitalized due to HIV, 15 newly diagnosed HIV cases had TB co-infection. Thirteen were included as subjects. Most patients (10/13) were under 5 years of age, with similar female and male proportions (7/13 vs. 6/13, respectively). All were diagnosed with stage 4 HIV. Six patients had respiratory problems at admission. First examinations revealed severe immunodeficiency (CD4+ <20%) in all patients, and high viral loads (>105 copies/mL) in most (9/13) patients. Despite good compliance to medications, 8/13 patients died before the sixth month follow-up. Deterioration of virologic and immunologic status was seen in 3/4 of the followed-up patients.
Conclusion Children with HIV-TB coinfections have severe immunodeficiency and high viral loads. Most such patients die before 6 months, while survivors experience virologic and immunologic status deterioration. Future study must take into account for HIV drug resistance investigation.
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Altfeld, Marcus, Eric S. Rosenberg, Raj Shankarappa, Joia S. Mukherjee, Frederick M. Hecht, Robert L. Eldridge, Marylyn M. Addo, et al. "Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection." Journal of Experimental Medicine 193, no. 2 (January 8, 2001): 169–80. http://dx.doi.org/10.1084/jem.193.2.169.
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Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.
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Lécuroux, Camille, Isabelle Girault, Alejandra Urrutia, Jean-Marc Doisne, Christiane Deveau, Cécile Goujard, Laurence Meyer, Martine Sinet, and Alain Venet. "Identification of a particular HIV-specific CD8+ T-cell subset with a CD27+ CD45RO−/RA+ phenotype and memory characteristics after initiation of HAART during acute primary HIV infection." Blood 113, no. 14 (April 2, 2009): 3209–17. http://dx.doi.org/10.1182/blood-2008-07-167601.
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AbstractCD8+ T cells play an important role in controlling viral infections. Defective CD8+ T-cell responses during HIV infection could contribute to viral persistence. Early initiation of highly active antiretroviral therapy during acute primary HIV infection helps to preserve HIV-specific immune responses. Here, we describe a particular CD27+ CD45RO−/RA+ HIV-specific CD8+ T cell in participants treated early during the primary infection. These cells, which were present at a very low frequency during primary HIV infection, increased markedly after early treatment, whereas their frequency remained unchanged in untreated participants and in participants treated later. These nonnaive antigen-experienced cells are in a resting state and have characteristics of long-lived memory cells. They also possess direct effector capabilities, such as cytokine production, and are able to proliferate and to acquire cytotoxic functions on reactivation. Our results suggest that these HIV-specific CD27+ CD45RO−/RA+ CD8+ T cells, observed when early viral replication is inhibited, form a pool of resting cells with memory characteristics.
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Sonmezoglu, Meral, Yesim Aydinok, Duran Canatan, Meral Turker, Huseyin Gulen, Gulersu Irken, Zeynep Karakas, et al. "Transfusion Transmitted Viral Infections in Transfusion Dependent Patients with Thalassemia in Turkey: A Multicenter Study." Blood 104, no. 11 (November 16, 2004): 3782. http://dx.doi.org/10.1182/blood.v104.11.3782.3782.
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Abstract Thalassemia Major (TM) represent one of the largest groups requiring regular transfusions lifelong. A total of 3830 patients are currently registered with homozygous b-Thalassemia in Turkey. This study is designated to reveal the seropositivity status of thalassemia patients on chronic transfusion treatment for blood-borne infections. A questionnaire inquiring the demographics and medical history of the patients as well as serological status for hepatitis B, C and HIV, was sent to 12 Thalassemia Centers which are generally settled down in the University or big government hospitals with high capacity blood banks where the packed red cells were provided. The collected data of 999 patients who have regular transfusions of 1–2 Unit red cells, every 3–4 weeks beginning from the first years of life and screened for transfusion transmitted viruses (TTV) 6 monthly was analyzed. The patients were aged between 0–53 years (median 16 years). Overall HBsAg and Anti-HCV positivity were found 2.5% and 12.6% respectively. Confirmed Anti-HIV positivity was 0.2% in the study group and consistent with the low frequency of the disease among blood donors in Turkey. Age distribution of sero-positivity within the patients was as follows: 0.7% in 0–5 years, 17% in 6–10 years, 48.3% in 11–20 years and 34% over 21 years, indicating the strong relation between the sero-prevalence of TTV and transfused blood volume and the gradually increased safety of blood in Turkey. The highest prevalence rate was seen in the age of 11–20 years which also represents highest number of patients. Donated blood screening for HBsAg, anti-HIV 1/2 (since 1985), anti-HCV (since1996), and RPR for syphilis is obliged by law in Turkey. Although, widespread use of HBV vaccination in transfusion dependent patients has been started since 1990s, the data confirmed that this measurement is insufficient alone for eradicating the HBV transmission in this group. Vaccination against HBV has been scheduled routine vaccination program of infancy by the health authority since 1999. However, the positive reflection of this policy in blood safety would be seen in the next generations. In that point of view, vaccination against hepatitis B can be practised in blood donors as a preventive measure in Turkey which is considered as in the middle endemic region regarding hepatitis B infection. Although, Anti-HCV screening in blood donors caused significant decrease in HCV infection, it still represents the main cause of morbidity following cardiomyopathy in this group of patients. This study clearly shows that the threat of TTV infections among multi-transfused thalassemia patients and underlines the importance of strengthen blood donor selection and implementing the sensitive screening assays for TTV at blood centers.
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Horton, Helen, Colin Havenar-Daughton, Deborah Lee, Erin Moore, Jianhong Cao, John McNevin, Thomas Andrus, et al. "Induction of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses in HIV Vaccine Trial Participants Who Subsequently Acquire HIV-1 Infection." Journal of Virology 80, no. 19 (October 1, 2006): 9779–88. http://dx.doi.org/10.1128/jvi.00794-06.
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ABSTRACT Candidate human immunodeficiency virus type 1 (HIV-1) vaccines designed to elicit T-cell immunity in HIV-1-uninfected persons are under investigation in phase I to III clinical trials. Little is known about how these vaccines impact the immunologic response postinfection in persons who break through despite vaccination. Here, we describe the first comprehensive characterization of HIV-specific T-cell immunity in vaccine study participants following breakthrough HIV-1 infection in comparison to 16 nonvaccinated subjects with primary HIV-1 infection. Whereas none of the 16 breakthrough infections possessed vaccine-induced HIV-1-specific T-cell responses preinfection, 85% of vaccinees and 86% of nonvaccinees with primary HIV-1 infection developed HIV-specific T-cell responses postinfection. Breakthrough subjects' T cells recognized 43 unique HIV-1 T-cell epitopes, of which 8 are newly described, and 25% were present in the vaccine. The frequencies of gamma interferon (IFN-γ)-secreting cells recognizing epitopes within gene products that were and were not encoded by the vaccine were not different (P = 0.64), which suggests that responses were not anamnestic. Epitopes within Nef and Gag proteins were the most commonly recognized in both vaccinated and nonvaccinated infected subjects. One individual controlled viral replication without antiretroviral therapy and, notably, mounted a novel HIV-specific HLA-C14-restricted Gag LYNTVATL-specific T-cell response. Longitudinally, HIV-specific T cells in this individual were able to secrete IFN-γ and tumor necrosis factor alpha, as well as proliferate and degranulate in response to their cognate antigenic peptides up to 5 years postinfection. In conclusion, a vaccinee's ability to mount an HIV-specific T-cell response postinfection is not compromised by previous immunization, since the CD8+ T-cell responses postinfection are similar to those seen in vaccine-naïve individuals. Finding an individual who is controlling infection highlights the importance of comprehensive studies of breakthrough infections in vaccine trials to determine whether host genetics/immune responses and/or viral characteristics are responsible for controlling viral replication.
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Kim, Arthur Y., Georg M. Lauer, Kei Ouchi, Marylyn M. Addo, Michaela Lucas, Julian Schulze zur Wiesch, Joerg Timm, et al. "The magnitude and breadth of hepatitis C virus–specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1." Blood 105, no. 3 (February 1, 2005): 1170–78. http://dx.doi.org/10.1182/blood-2004-06-2336.
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AbstractCD8+ T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4+ T-helper cells. To determine the relationship between HIV-1–induced CD4+ T-cell depletion and hepatitis C virus (HCV)–specific CD8+ T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8+ T-cell responses to the entire HCV polyprotein were determined by using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1–associated CD4+ depletion was associated with significantly lower HCV-specific CD8+ T cells (R = 0.48, P < .0001). In contrast, declining CD4+ counts over the same range were not associated with diminished Epstein-Barr virus (EBV)– (R = 0.19, P = .31) or HIV-1–specific (R = –0.13, P = .60) CD8+ T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8+ T-cell responses are sensitive to absolute CD4+ T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.
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Tang, Qiyi, Nadia R. Roan, and Yasuhiro Yamamura. "Seminal Plasma and Semen Amyloids Enhance Cytomegalovirus Infection in Cell Culture." Journal of Virology 87, no. 23 (September 11, 2013): 12583–91. http://dx.doi.org/10.1128/jvi.02083-13.
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Among the modes of transmission available to the cytomegalovirus (CMV) is sexual transmission, primarily via semen. Both male-to-female (M-F) and male-to-male (M-M) sexual transmission significantly contribute toward the spread of CMV infections in the global population. Semen plays an important role in carrying the viral particle that invades the vaginal or rectal mucosa, thereby initiating viral replication. Both semen and seminal plasma (SP) can enhance HIV-1 infection in cell culture, and two amyloid fibrils, semen-derived enhancer of viral infection (SEVI) and amyloids derived from the semenogelins (SEM amyloids), have been identified as seminal factors sufficient to enhance HIV-1 infection (J. Munch et al., Cell131:1059–1071, 2007; N. R. Roan et al., Cell Host Microbe10:541–550, 2011; F. Arnold et al., J. Virol. 86:1244–1249, 2012). Whether SP, SEVI, or SEM amyloids can enhance other viral infections has not been extensively examined. In this study, we found that SP, SEVI, and SEM amyloids strongly enhance both human CMV (HCMV) and murine CMV infection in cell culture. SEVI and SEM amyloids increased infection rates by >10-fold, as determined by both flow cytometry and fluorescence microscopy. Viral replication was increased by 50- to 100-fold. Moreover, viral growth curve assays showed that SP, SEVI, and SEM amyloids sped up the kinetics of CMV replication such that the virus reached its replicative peak more quickly. Finally, we discovered that SEM amyloids and SEVI counteracted the effect of anti-gH in protecting against CMV infection. Collectively, the data suggest that semen enhances CMV infection through interactions between semen amyloid fibrils and viral particles, and these interactions may prevent HCMV from being neutralized by anti-gH antibody.
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Dong, Chunsheng, Alicia M. Janas, Jian-Hua Wang, Wendy J. Olson, and Li Wu. "Characterization of Human Immunodeficiency Virus Type 1 Replication in Immature and Mature Dendritic Cells Reveals Dissociable cis- and trans-Infection." Journal of Virology 81, no. 20 (August 8, 2007): 11352–62. http://dx.doi.org/10.1128/jvi.01081-07.
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ABSTRACT Dendritic cells (DCs) transmit human immunodeficiency virus type 1 (HIV-1) to CD4+ T cells through the trans- and cis-infection pathways; however, little is known about the relative efficiencies of these pathways and whether they are interdependent. Here we compare cis- and trans-infections of HIV-1 mediated by immature DCs (iDCs) and mature DCs (mDCs), using replication-competent and single-cycle HIV-1. Monocyte-derived iDCs were differentiated into various types of mDCs by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-α), and CD40 ligand (CD40L). iDCs and CD40L-induced mDCs were susceptible to HIV-1 infection and mediated efficient viral transmission to CD4+ T cells. Although HIV-1 cis-infection was partially restricted in TNF-α-induced mDCs and profoundly blocked in LPS-induced mDCs, these cells efficiently promoted HIV-1 trans-infection of CD4+ T cells. The postentry restriction of HIV-1 infection in LPS-induced mDCs was identified at the levels of reverse transcription and postintegration, using real-time PCR quantification of viral DNA and integration. Furthermore, nucleofection of DCs with HIV-1 proviral DNA confirmed that impaired gene expression of LPS-induced mDCs was responsible for the postentry restriction of HIV-1 infection. Our results suggest that various DC subsets in vivo may differentially contribute to HIV-1 dissemination via dissociable cis- and trans-infections.
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Cannon, PM, DG Tenen, MB Feinberg, HS Shin, and S. Kim. "Human immunodeficiency virus-1 infection of the human promyelocytic cell line HL-60: high frequency of low-level infection and effect of subsequent cell differentiation." Blood 81, no. 2 (January 15, 1993): 437–45. http://dx.doi.org/10.1182/blood.v81.2.437.437.
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Abstract As a model system to study the infection of early myeloid cells by human immunodeficiency virus-1 (HIV-1), we have infected the human promyelocytic cell line, HL-60, with a recombinant selectable HIV-1 clone. A fully infected population showed a relatively high frequency of low-level infection, with 40% of subcloned cells being negative by reverse transcriptase and p24 indirect immunofluorescence analysis and displaying only low levels of supernatant p24. The same treatment of a T-lymphoid cell line produced 100% productive infections. HIV-1 infection of HL-60 did not appear to alter the state of differentiation of the cells, as assessed by surface antigen expression, regardless of the level of viral expression. Furthermore, infected cells were able to respond normally to chemical inducers of differentiation. Induction of differentiation towards monocyte/macrophages by phorbol myristate acetate activated the HIV-1 long terminal repeat in a transient transfection system, and there was a corresponding increase in viral production from the infected subclones. Granulocytic differentiation, as stimulated by dimethyl sulfoxide or retinoic acid, had no effect on long terminal repeat activity and did not stimulate viral replication. These data suggest that low-level HIV-1 infections may be established at a relatively high frequency in myeloid precursor cells, and that different pathways of promyelocytic differentiation vary in their ability to stimulate HIV-1 replication.
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Cannon, PM, DG Tenen, MB Feinberg, HS Shin, and S. Kim. "Human immunodeficiency virus-1 infection of the human promyelocytic cell line HL-60: high frequency of low-level infection and effect of subsequent cell differentiation." Blood 81, no. 2 (January 15, 1993): 437–45. http://dx.doi.org/10.1182/blood.v81.2.437.bloodjournal812437.
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As a model system to study the infection of early myeloid cells by human immunodeficiency virus-1 (HIV-1), we have infected the human promyelocytic cell line, HL-60, with a recombinant selectable HIV-1 clone. A fully infected population showed a relatively high frequency of low-level infection, with 40% of subcloned cells being negative by reverse transcriptase and p24 indirect immunofluorescence analysis and displaying only low levels of supernatant p24. The same treatment of a T-lymphoid cell line produced 100% productive infections. HIV-1 infection of HL-60 did not appear to alter the state of differentiation of the cells, as assessed by surface antigen expression, regardless of the level of viral expression. Furthermore, infected cells were able to respond normally to chemical inducers of differentiation. Induction of differentiation towards monocyte/macrophages by phorbol myristate acetate activated the HIV-1 long terminal repeat in a transient transfection system, and there was a corresponding increase in viral production from the infected subclones. Granulocytic differentiation, as stimulated by dimethyl sulfoxide or retinoic acid, had no effect on long terminal repeat activity and did not stimulate viral replication. These data suggest that low-level HIV-1 infections may be established at a relatively high frequency in myeloid precursor cells, and that different pathways of promyelocytic differentiation vary in their ability to stimulate HIV-1 replication.
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DiNapoli, Sarah R., Vanessa M. Hirsch, and Jason M. Brenchley. "Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections." Journal of Virology 90, no. 17 (June 15, 2016): 7596–606. http://dx.doi.org/10.1128/jvi.00672-16.
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The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infectedin vivoare memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replicationin vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophagesin vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus.
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Kuntzen, Thomas, Joerg Timm, Andrew Berical, Lia L. Lewis-Ximenez, Andrea Jones, Brian Nolan, Julian Schulze zur Wiesch, et al. "Viral Sequence Evolution in Acute Hepatitis C Virus Infection." Journal of Virology 81, no. 21 (August 15, 2007): 11658–68. http://dx.doi.org/10.1128/jvi.00995-07.
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ABSTRACT CD8+-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+-T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total nonenvelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of nonenvelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.
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Sayed, Ibrahim M., Mohamed Ismail Seddik, Marwa A. Gaber, Saber H. Saber, Sahar A. Mandour, and Mohamed A. El-Mokhtar. "Replication of Hepatitis E Virus (HEV) in Primary Human-Derived Monocytes and Macrophages In Vitro." Vaccines 8, no. 2 (May 21, 2020): 239. http://dx.doi.org/10.3390/vaccines8020239.
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HEV is the most causative agent of acute viral hepatitis globally. HEV causes acute, chronic, and extrahepatic manifestations. Chronic HEV infection develops in immunocompromised patients such as organ transplant patients, HIV-infected patients, and leukemic patients. The source of chronic HEV infection is not known. Also, the source of extrahepatic manifestations associated with HEV infection is still unclear. Hepatotropic viruses such as HCV and HBV replicate in peripheral blood mononuclear cells (PBMCs) and these cells become a source of chronic reactivation of the infections in allograft organ transplant patients. Herein, we reported that PBMCs and bone marrow-derived macrophages (BMDMs), isolated from healthy donors (n = 3), are susceptible to HEV in vitro. Human monocytes (HMOs), human macrophages (HMACs), and human BMDMs were challenged with HEV-1 and HEV-3 viruses. HEV RNA was measured by qPCR, the marker of the intermediate replicative form (ds-RNA) was assessed by immunofluorescence, and HEV capsid protein was assessed by flow cytometry and ELISA. HEV infection was successfully established in primary HMOs, HMACs, and human BMDMs, but not in the corresponding cells of murine origin. Intermediate replicative form (ds RNA) was detected in HMOs and HMACs challenged with HEV. The HEV load was increased over time, and the HEV capsid protein was detected intracellularly in the HEV-infected cells and accumulated extracellularly over time, confirming that HEV completes the life cycle inside these cells. The HEV particles produced from the infected BMDMs were infectious to naive HMOs in vitro. The HEV viral load was comparable in HEV-1- and HEV-3-infected cells, but HEV-1 induced more inflammatory responses. In conclusion, HMOs, HMACs, and human BMDMs are permissive to HEV infection and these cells could be the source of chronic and recurrent infection, especially in immunocompromised patients. Replication of HEV in human BMDMs could be related to hematological disorders associated with extrahepatic manifestations.
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Khurana, Surender, James Needham, Bonnie Mathieson, Isaac R. Rodriguez-Chavez, Andrew T. Catanzaro, Robert T. Bailer, Jerome Kim, et al. "Human Immunodeficiency Virus (HIV) Vaccine Trials: a Novel Assay for Differential Diagnosis of HIV Infections in the Face of Vaccine-Generated Antibodies." Journal of Virology 80, no. 5 (March 1, 2006): 2092–99. http://dx.doi.org/10.1128/jvi.80.5.2092-2099.2006.
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ABSTRACT All current human immunodeficiency virus (HIV) vaccine candidates contain multiple viral components and elicit antibodies that react positively in licensed HIV diagnostic tests, which contain similar viral products. Thus, vaccine trial participants could be falsely diagnosed as infected with HIV. Additionally, uninfected, seropositive vaccinees may encounter long-term social and economic harms. Moreover, this also interferes with early detection of true HIV infections during preventive HIV vaccine trials. An HIV-seropositive test result among uninfected vaccine trial participants is a major public health concern for volunteers who want to participate in future HIV vaccine trials. Based on the increased number of HIV vaccines being tested globally, it is essential to differentiate vaccine- from virus-induced antibodies. Using a whole-HIV-genome phage display library, we identified conserved sequences in Env-gp41 and Gag-p6 which are recognized soon after infection, do not contain protective epitopes, and are not part of most current HIV vaccines. We established a new HIV serodetection assay based on these peptides. To date, this assay, termed HIV-SELECTEST, demonstrates >99% specificity and sensitivity. Importantly, in testing of plasma samples from multiple HIV vaccine trials, uninfected trial participants scored negative, while all intercurrent infections were detected within 1 to 3 months of HIV infection. The new HIV-SELECTEST is a simple but robust diagnostic tool for easy implementation in HIV vaccine trials and blood banks worldwide.
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BUTCHER, G. A. "T-cell depletion and immunity to malaria in HIV-infections." Parasitology 130, no. 2 (October 13, 2004): 141–50. http://dx.doi.org/10.1017/s003118200400650x.
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Although early reports on HIV and malaria in co-infected subjects indicated little apparent interaction between the two infections, more recent investigations have found evidence for HIV increasing the risk from malaria. Conversely, increased viral load in susceptible cells occurs in malaria-infected people. However, the overall pattern of results is still somewhat confusing and contradictory. While morbidity from malaria may be greater in HIV-positive patients and in several reports the mortality risk is also higher, major increases in blood-stage parasitaemias that one might expect are not generally observed. The results of surveys are summarized and discussed in the context of what is known of malaria and HIV immunology in the light of recent data from humans as well as animal models.
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Draenert, Rika, Todd M. Allen, Yang Liu, Terri Wrin, Colombe Chappey, Cori L. Verrill, Guillem Sirera, et al. "Constraints on HIV-1 evolution and immunodominance revealed in monozygotic adult twins infected with the same virus." Journal of Experimental Medicine 203, no. 3 (March 13, 2006): 529–39. http://dx.doi.org/10.1084/jem.20052116.
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The predictability of virus–host interactions and disease progression in rapidly evolving human viral infections has been difficult to assess because of host and genetic viral diversity. Here we examined adaptive HIV-specific cellular and humoral immune responses and viral evolution in adult monozygotic twins simultaneously infected with the same virus. CD4 T cell counts and viral loads followed similar trajectories over three years of follow up. The initial CD8 T cell response targeted 17 epitopes, 15 of which were identical in each twin, including two immunodominant responses. By 36 months after infection, 14 of 15 initial responses were still detectable in both, whereas all new responses were subdominant and remained so. Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin's virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.
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Harouse, Janet M., Agegnehu Gettie, Tadesse Eshetu, Rei Chin How Tan, Rudolf Bohm, James Blanchard, Gary Baskin, and Cecilia Cheng-Mayer. "Mucosal Transmission and Induction of Simian AIDS by CCR5-Specific Simian/Human Immunodeficiency Virus SHIVSF162P3." Journal of Virology 75, no. 4 (February 15, 2001): 1990–95. http://dx.doi.org/10.1128/jvi.75.4.1990-1995.2001.
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ABSTRACT Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIVSF162P3. Female rhesus macaques were infected with SHIVSF162P3 after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIVSF162P3-infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4+ peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIVSF162P3/macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.
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Wahid, Braira, Amjad Ali, Muhammad Idrees, and Shazia Rafique. "Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV." Cellular Immunology 310 (December 2016): 1–13. http://dx.doi.org/10.1016/j.cellimm.2016.08.001.
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Barugahare, Banson, Chris Baker, Okumu K'Aluoch, Richard Donovan, Mohamed Elrefaei, Mark Eggena, Norman Jones, et al. "Human Immunodeficiency Virus-Specific Responses in Adult Ugandans: Patterns of Cross-Clade Recognition." Journal of Virology 79, no. 7 (April 1, 2005): 4132–39. http://dx.doi.org/10.1128/jvi.79.7.4132-4139.2005.
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ABSTRACT Human immunodeficiency virus (HIV) or AIDS is currently the leading cause of death in Uganda, with at least three HIV clades (subtypes) accounting for most new infections. Whether an effective vaccine formulated on viruses from a single clade will be able to protect against infection from other local clades remains unresolved. We examined the T-cell immune responses from a cohort of HIV-seropositive individuals in Uganda with predominantly clade A and D infections. Surprisingly, we observed similar frequencies of cross-clade T-cell responses to the gag, env, and nef regions. Our data suggest that the level of viral sequence variability between distinct HIV strains does not predict the degree of cross-clade responses. High sequence homologies were also observed between consensus peptides and sequences from viral isolates, supporting the use of consensus amino acid sequences to identify immunogenic regions in studies of large populations.
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Reuter, Morgan A., Nicole D. Pecora, Clifford V. Harding, David H. Canaday, and David McDonald. "Mycobacterium tuberculosis Promotes HIV trans-Infection and Suppresses Major Histocompatibility Complex Class II Antigen Processing by Dendritic Cells." Journal of Virology 84, no. 17 (June 30, 2010): 8549–60. http://dx.doi.org/10.1128/jvi.02303-09.
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ABSTRACT Mycobacterium tuberculosis is a leading killer of HIV-infected individuals worldwide, particularly in sub-Saharan Africa, where it is responsible for up to 50% of HIV-related deaths. Infection by HIV predisposes individuals to M. tuberculosis infection, and coinfection accelerates the progression of both diseases. In contrast to most other opportunistic infections associated with HIV, an increased risk of M. tuberculosis infection occurs during early-stage HIV disease, long before CD4 T cell counts fall below critical levels. We hypothesized that M. tuberculosis infection contributes to HIV pathogenesis by interfering with dendritic cell (DC)-mediated immune control. DCs carry pathogens like M. tuberculosis and HIV from sites of infection into lymphoid tissues, where they process and present antigenic peptides to CD4 T cells. Paradoxically, DCs can also deliver infectious HIV to T cells without first becoming infected, a process known as trans-infection. Lipopolysaccharide (LPS)-activated DCs sequester HIV in pocketlike membrane invaginations that remain open to the cell surface, and individual virions are delivered from the pocket into T cells at the site of contact during trans-infection. Here we report that M. tuberculosis exposure increases HIV trans-infection and induces viral sequestration within surface-accessible compartments identical to those seen in LPS-stimulated DCs. At the same time, M. tuberculosis dramatically decreases the degradative processing and major histocompatibility complex class II (MHC-II) presentation of HIV antigens to CD4 T cells. Our data suggest that M. tuberculosis infection promotes a shift in the dynamic balance between antigen processing and intact virion presentation, favoring DC-mediated amplification of HIV infections.
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Little, Susan J., Angela R. McLean, Celsa A. Spina, Douglas D. Richman, and Diane V. Havlir. "Viral Dynamics of Acute HIV-1 Infection." Journal of Experimental Medicine 190, no. 6 (September 20, 1999): 841–50. http://dx.doi.org/10.1084/jem.190.6.841.
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Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R0), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (α) was highly variable among individuals. The phase 1 viral decay rate (δI = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R0) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection.
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Nunes-Cabaço, Helena, Paula Matoso, Russell B. Foxall, Rita Tendeiro, Ana R. Pires, Tânia Carvalho, Ana I. Pinheiro, Rui S. Soares, and Ana E. Sousa. "Thymic HIV-2 Infection Uncovers Posttranscriptional Control of Viral Replication in Human Thymocytes." Journal of Virology 89, no. 4 (December 3, 2014): 2201–8. http://dx.doi.org/10.1128/jvi.03047-14.
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ABSTRACTA unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control.IMPORTANCEHIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.
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Kumar, Amit, Wasim Abbas, and Georges Herbein. "TNF and TNF Receptor Superfamily Members in HIV infection: New Cellular Targets for Therapy?" Mediators of Inflammation 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/484378.
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Tumor necrosis factor (TNF) and TNF receptors (TNFR) superfamily members are engaged in diverse cellular phenomena such as cellular proliferation, morphogenesis, apoptosis, inflammation, and immune regulation. Their role in regulating viral infections has been well documented. Viruses have evolved with numerous strategies to interfere with TNF-mediated signaling indicating the importance of TNF and TNFR superfamily in viral pathogenesis. Recent research reports suggest that TNF and TNFRs play an important role in the pathogenesis of HIV. TNFR signaling modulates HIV replication and HIV proteins interfere with TNF/TNFR pathways. Since immune activation and inflammation are the hallmark of HIV infection, the use of TNF inhibitors can have significant impact on HIV disease progression. In this review, we will describe how HIV infection is modulated by signaling mediated through members of TNF and TNFR superfamily and in turn how these latter could be targeted by HIV proteins. Finally, we will discuss the emerging therapeutics options based on modulation of TNF activity that could ultimately lead to the cure of HIV-infected patients.
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Yamashita, Masahiro, and Michael Emerman. "Cellular Restriction Targeting Viral Capsids Perturbs Human Immunodeficiency Virus Type 1 Infection of Nondividing Cells." Journal of Virology 83, no. 19 (July 22, 2009): 9835–43. http://dx.doi.org/10.1128/jvi.01084-09.
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ABSTRACT The ability of human immunodeficiency virus (HIV) to infect nondividing cells is a fundamental property by which HIV replicates in critical target cells, such as macrophages and resting CD4+ T cells. Recent studies have revealed that the capsid (CA) protein is a dominant factor that determines retrovirus infectivity in nondividing cells, and several mutations in HIV type 1 (HIV-1) CA abrogate the ability of HIV-1 to infect nondividing cells. We present evidence for a connection between cellular restriction against viral capsids and the resistance of nondividing cells to retrovirus infection. TRIM proteins that are able to target incoming viral capsids restrict HIV-1 more potently in nondividing cells than in dividing cells, thus rendering HIV-1 infection dependent on cell division. Moreover, cyclophilin A, another cellular protein that binds to HIV-1 CA, regulates HIV-1 infection of nondividing cells. Together, these data demonstrate the importance of capsid-binding cellular proteins in the control of the cell cycle independence of HIV-1. We propose that cellular restrictions to retroviral infections are themselves cell cycle dependent.
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Jiang, Ai-Ping, Jin-Feng Jiang, Ming-Gao Guo, Yong-Mei Jin, Yu-Ye Li, and Jian-Hua Wang. "Human Blood-Circulating Basophils Capture HIV-1 and Mediate Viraltrans-Infection of CD4+T Cells." Journal of Virology 89, no. 15 (May 27, 2015): 8050–62. http://dx.doi.org/10.1128/jvi.01021-15.
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ABSTRACTCell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Granulocytes are a category of white blood cells, comprising mainly basophils, neutrophils, and eosinophils, and participate in various inflammatory reactions and defense against pathogens. Here, we investigated the role of human blood granulocytes in the dissemination of HIV-1. These cells were found to express a variety of HIV-1 attachment factors (HAFs). Basophils expressed HAFs dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM3)-grabbing nonintegrin (DC-SIGN), DC immunoreceptor (DCIR), heparan sulfate proteoglycan (HSPG), and α4β7 integrin and mediated the most efficient capture of HIV-1 on the cell surface. Neutrophils were found to express DCIR and demonstrated limited efficiency of viral capture. Eosinophils expressed α4β7 integrin but exhibited little or no virus-binding capacity. Intriguingly, following direct contact with CD4+T cells, viruses harbored on the surface of basophils were transferred to T cells. The contact between basophils and CD4+T cells and formation of infectious synapses appeared necessary for efficient HIV-1 spread. In HIV-1-infected individuals, the frequency of basophils remained fairly stable over the course of disease, regardless of CD4+T depletion or the emergence of AIDS-associated opportunistic infections. Collectively, our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. Thus, strategies designed to prevent basophil-mediated viral capture and transfer may be developed into a new form of therapy.IMPORTANCECell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Here, we demonstrated that human blood-circulating granulocytes, particularly basophils, can capture HIV-1 and mediate viraltrans-infection of CD4+T cells. The expression of a variety of HIV-1 attachment factors, such as the C-type lectins, etc., facilitates viral capture and transfer. Intriguingly, the frequency of basophils in patients with different levels of CD4+T counts remains fairly stable during the course of disease. Our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. We suggest that strategies designed to prevent basophil-mediated viral capture and transfer may be a new direction for the development of anti-HIV therapy.
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Rodriguez, Shaun K., Abdoulaye Dieng Sarr, Adam MacNeil, Seema Thakore-Meloni, Aissatou Gueye-Ndiaye, Ibrahima Traoré, Mamadou C. Dia, Souleymane Mboup, and Phyllis J. Kanki. "Comparison of Heterologous Neutralizing Antibody Responses of Human Immunodeficiency Virus Type 1 (HIV-1)- and HIV-2-Infected Senegalese Patients: Distinct Patterns of Breadth and Magnitude Distinguish HIV-1 and HIV-2 Infections." Journal of Virology 81, no. 10 (February 14, 2007): 5331–38. http://dx.doi.org/10.1128/jvi.02789-06.
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ABSTRACT Neutralizing antibody responses against heterologous isolates in human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections were compared, and their relationships with established clinical markers of progression were examined. Neutralizing responses against 7 heterologous primary isolates and 1 laboratory strain were compared between 32 untreated HIV-1-infected subjects and 35 untreated HIV-2-infected subjects using a pseudotyped reporter virus assay. The breadth of the neutralizing response, defined as the proportion of panel viruses positively neutralized by patient plasma, was significantly greater among HIV-2-infected subjects than among HIV-1-infected subjects. Notably, for fully one-third of HIV-2 subjects, all viruses were effectively neutralized in our panel. Magnitudes of responses, defined as reciprocal 50% inhibitory concentration (IC50) titers for positive reactions, were significantly greater among HIV-1-infected subjects than among HIV-2-infected subjects. When plasma samples from HIV-1 patients were tested for cross-neutralization of HIV-2 and vice versa, we found that these intertype responses are very rare and their prevalences comparable in both HIV-1 and HIV-2 infection. The significantly higher magnitude of heterologous responses for HIV-1 compared to HIV-2 prompted us to examine associations with viremia, which is known to be significantly higher in HIV-1 infection. Importantly, there was a significant positive correlation between the IC50 titer and viral load within both the HIV-1 and HIV-2 groups, suggesting heterologous antibodies may be driven by viral replication. We conclude that HIV-2 infection is characterized by a broad, low-magnitude intratype neutralization response, while HIV-1 is characterized by a narrower but higher-magnitude intratype response and that a significant positive association between the IC50 titer and viremia is common to both HIV-1 and HIV-2 infections.
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Alter, Galit, Nickolas Teigen, Benjamin T. Davis, Marylyn M. Addo, Todd J. Suscovich, Michael T. Waring, Hendrik Streeck, et al. "Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection." Blood 106, no. 10 (November 15, 2005): 3366–69. http://dx.doi.org/10.1182/blood-2005-03-1100.
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AbstractNatural killer (NK) cells are critical in the first-line defense against viral infections. Chronic HIV-1 infection leads to a perturbation in the NK cell compartment, yet the kinetics of this deregulation and the functional consequences are unclear. Here, we characterized changes in the NK cell compartment longitudinally by multiparameter flow cytometry, starting in acute HIV-1 infection. Acute HIV-1 infection was associated with elevated NK cell numbers, with an expansion of CD3negCD56dimCD16pos NK cells and an early depletion of CD3negCD56brightCD16neg NK cells. Ongoing viral replication resulted in a depletion of CD3negCD56dimCD16pos NK cells with a paralleled increase in functionally anergic CD3negCD56negCD16pos NK cells, accompanied by reduced functional activity, as measured by CD107a expression and cytokine secretion. Taken together, these studies demonstrate a sequential impairment of NK cell function with persistent viral replication resulting from a progressive deregulation of NK cell subsets with distinct functional properties.
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Frater, A. J., C. T. T. Edwards, N. McCarthy, J. Fox, H. Brown, A. Milicic, N. Mackie, et al. "Passive Sexual Transmission of Human Immunodeficiency Virus Type 1 Variants and Adaptation in New Hosts." Journal of Virology 80, no. 14 (July 15, 2006): 7226–34. http://dx.doi.org/10.1128/jvi.02014-05.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences.
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Schellenberg, John J., and Francis A. Plummer. "The Microbiological Context of HIV Resistance: Vaginal Microbiota and Mucosal Inflammation at the Viral Point of Entry." International Journal of Inflammation 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/131243.
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Immune activation is increasingly recognized as a critical element of HIV infection and pathogenesis, causing expansion of virus founder populations at the mucosal port of entry and eventual exhaustion of cellular immune effectors. HIV susceptibility is well known to be influenced by concurrent sexually transmitted infections; however, the role of commensal vaginal microbiota is poorly characterized. Bacterial vaginosis (BV) is a risk factor for HIV acquisition in studies worldwide; however, the etiology of BV remains enigmatic, and the mechanisms by which BV increases HIV susceptibility are not fully defined. A model of how vaginal microbiota influences HIV transmission is considered in the context of a well-established cohort of HIV-exposed seronegative (HESN) commercial sex workers (CSW) in Nairobi, Kenya, many of whom have increased levels of anti-inflammatory factors in vaginal secretions and reduced peripheral immune activation (immune quiescence). Elucidation of the relationship between complex microbial communities and inflammatory mucosal responses underlying HIV infection should be a priority for future prevention-focussed research.
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Alter, Galit, Suzannah Rihn, Katharine Walter, Anne Nolting, Maureen Martin, Eric S. Rosenberg, Jeffrey S. Miller, Mary Carrington, and Marcus Altfeld. "HLA Class I Subtype-Dependent Expansion of KIR3DS1+ and KIR3DL1+ NK Cells during Acute Human Immunodeficiency Virus Type 1 Infection." Journal of Virology 83, no. 13 (April 22, 2009): 6798–805. http://dx.doi.org/10.1128/jvi.00256-09.
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ABSTRACT NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of human immunodeficiency virus type 1 (HIV-1) infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. Here we demonstrate that NK cells expressing the activating receptor KIR3DS1+ and, to a lesser extent, the inhibitory receptor KIR3DL1+ specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. These data demonstrate for the first time the HLA class I subtype-dependent expansion of specific KIR+ NK cells during an acute viral infection in humans.
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Lichterfeld, Mathias, Xu G. Yu, Stanley K. Mui, Katie L. Williams, Alicja Trocha, Mark A. Brockman, Rachel L. Allgaier, et al. "Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells after Early HIV-1 Infection." Journal of Virology 81, no. 8 (February 7, 2007): 4199–214. http://dx.doi.org/10.1128/jvi.01388-06.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.