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Ayala-Suárez, Rubén, Francisco Díez-Fuertes, Esther Calonge, Humberto Erick De La Torre Tarazona, María Gracia-Ruíz de Alda, Laura Capa, and José Alcamí. "Insight in miRNome of Long-Term Non-Progressors and Elite Controllers Exposes Potential RNAi Role in Restraining HIV-1 Infection." Journal of Clinical Medicine 9, no. 8 (July 31, 2020): 2452. http://dx.doi.org/10.3390/jcm9082452.
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Long-term non-progressors (LTNP) and elite controllers (EC) represent spontaneous natural models of efficient HIV-1 response in the absence of treatment. The main purposes of this work are to describe the miRNome of HIV-1 infected patients with different extreme phenotypes and identify potentially altered pathways regulated by differentially expressed (DE) miRNAs. The miRNomes from peripheral blood mononuclear cells (PBMCs) of dual phenotype EC-LTNP or LTNP with detectable viremia and HIV-infected patients with typical progression before and after treatment, were obtained through miRNA-Seq and compared among them. The administration of treatment produces 18 DE miRNAs in typical progressors. LTNP condition shows 14 DE miRNA when compared to typical progressors, allowing LTNP phenotype differentiation. A set of four miRNAs: miR-144-3p, miR-18a-5p, miR-451a, and miR-324 is strongly downregulated in LTNP and related to protein regulation as AKT, mTOR, ERK or IKK, involved in immune response pathways. Deregulation of 28 miRNA is observed between EC-LTNP and viremic-LTNP, including previously described anti-HIV miRNAs: miR-29a, associated with LTNP phenotype, and miR-155, targeting different pre-integration complexes such as ADAM10 and TNPO3. A holistic perspective of the changes observed in the miRNome of patients with different phenotypes of HIV-control and non-progression is provided.
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Swathirajan, Chinnambedu Ravichandran, Ramachandran Vignesh, Greer Waldrop, Uma Shanmugasundaram, Pannerselvam Nandagopal, Sunil Suhas Solomon, Amrose Pradeep, Shanmugam Saravanan, and Kailapuri Gangatharan Murugavel. "HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India." Current HIV Research 16, no. 4 (January 14, 2019): 302–14. http://dx.doi.org/10.2174/1570162x17666181212122607.
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Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.
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Michel, Katherine Gisella, Bing Ma, Kathleen Weber, Leah McClellan, Anandi Sheth, Stephen Gange, Audrey French, Jacques Ravel, Igho Ofotokun, and Daniel Merenstein. "4117 UNIQUE VAGINAL MICROBIOME POPULATIONS AND MICROBIAL GENE CONTENT AMONG WOMEN WHO NATURALLY CONTROL HIV PROGRESSION." Journal of Clinical and Translational Science 4, s1 (June 2020): 20–21. http://dx.doi.org/10.1017/cts.2020.102.
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OBJECTIVES/GOALS: The role of the vaginal microbiome (VM) in HIV disease progression is poorly understood. We examined VMs of HIV+ Elite Controllers (ECs) and HIV+ Long-Term Non-Progressors (LTNPs) compared to controls: HIV-positive antiretroviral (ARV) treated (HIV+ATs) and HIV-negative women in the Women’s Interagency HIV Study (DC/Chicago/Atlanta sites). METHODS/STUDY POPULATION: VMs were surveyed via both V3/V4 region of 16S rRNA gene amplicon sequencing and metagenomics sequencing in 67 women across 4 study groups: 1) LTNPs (CD4 >500 cells/mL for 5+ years without ARVs) (n = 7) and 2) ECs (HIV RNA <80 copies/mL for 2+ years without ARVs) (n = 8), matched with 3) HIV+ ATs (on ARVs for ≥1 year with CD4 increase ≥100 cells/mm3) (n = 34), and 4) HIV- women (n = 18). Metagenomes were characterized from specimens collected at two time points: 1) vaginal swabs collected 2016-2017 (n = 62) and 2) cervicovaginal lavage collected 2002-2016 (n = 35; DC/Chicago only). We used VIRGO (human vaginal non-redundant gene catalog), a newly developed referencing framework to comprehensively catalog VM gene content, taxonomy and functions. RESULTS/ANTICIPATED RESULTS: Women were 89% African American with a mean age of 46 years (SD 8.8). The most prevalent species were Gardnerella vaginalis (predominant in 34%), Lactobacillus iners (predominant in 21%), and L. crispatus (predominant in 14%). 90% of LTNP and 45% of EC samples were Lactobacillus-dominant vs. 28% of HIV- and 30% of HIV+ATs. L. crispatus and L. iners in ECs/LTNPs had significantly different gene content and greater gene richness vs. controls. G. vaginalis-predominant communities were found in 66% of HIV- and 68% of HIV+ATs, compared to 46% of EC and 0% of LTNP. The G. vaginalis strains present in EC/LTNP also showed significantly lower gene richness and different gene content vs. controls. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest unique VM communities among EC/LTNP, and led us to hypothesize that differential regulation of vaginal immunity drives the observed differences. The similarity between VMs of HIV- and HIV+ATs warrants further study. Larger longitudinal VM studies are needed to assess associated functional pathways and understand the etiology of VM association with HIV progression. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose.
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Panoutsakopoulou, Vily, Kathryn Hunter, Thomas G. Sieck, Elizabeth P. Blankenhorn, and Kenneth J. Blank. "Genetic Regulation of Long-Term Nonprogression in E-55+ Murine Leukemia Virus Infection in Mice." Journal of Virology 73, no. 11 (November 1, 1999): 9232–36. http://dx.doi.org/10.1128/jvi.73.11.9232-9236.1999.
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ABSTRACT Certain inbred mouse strains display progression to lymphoma development after infection with E-55+ murine leukemia virus (E-55+ MuLV), while others demonstrate long-term nonprogression. This difference in disease progression occurs despite the fact that E-55+ MuLV causes persistent infection in both immunocompetent BALB/c–H-2k (BALB.K) progressor (P) and C57BL/10–H-2k (B10.BR) long-term nonprogressor (LTNP) mice. In contrast to immunocompetent mice, immunosuppressed mice from both P and LTNP strains develop lymphomas about 2 months after infection, indicating that the LTNP phenotype is determined by the immune response of the infected mouse. In this study, we used bone marrow chimeras to demonstrate that the LTNP phenotype is associated with the genotype of donor bone marrow and not the recipient microenvironment. In addition, we have mapped a genetic locus that may be responsible for the LTNP trait. Microsatellite-based linkage analysis demonstrated that a non-major histocompatibility complex gene on chromosome 15 regulates long-term survival and is located in the same region as the Rfv3 gene. Rfv3 is involved in recovery from Friend virus-induced leukemia and has been demonstrated to regulate neutralizing virus antibody titers. In our studies, however, both P and LTNP strains produce similar titers of neutralizing and cytotoxic anti-E-55+ MuLV. Therefore, while it is possible that Rfv3 influences the course of E-55+ MuLV infection, it is more likely that the LTNP phenotype in E-55+ MuLV-infected mice is regulated by a different, closely linked gene.
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Pushker, Ravindra, Jean-Marc Jacqué, and Denis C. Shields. "Meta-Analysis To Test the Association of HIV-1 nef Amino Acid Differences and Deletions with Disease Progression." Journal of Virology 84, no. 7 (January 13, 2010): 3644–53. http://dx.doi.org/10.1128/jvi.01959-09.
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ABSTRACT Previous relatively small studies have associated particular amino acid replacements and deletions in the HIV-1 nef gene with differences in the rate of HIV disease progression. We tested more rigorously whether particular nef amino acid differences and deletions are associated with HIV disease progression. Amino acid replacements and deletions in patients' consensus sequences were investigated for 153 progressor (P), 615 long-term nonprogressor (LTNP), and 2,311 unknown progressor sequences from 582 subtype B HIV-infected patients. LTNPs had more defective nefs (interrupted by frameshifts or stop codons), but on a per-patient basis there was no excess of LTNP patients with one or more defective nef sequences compared to the Ps (P = 0.47). The high frequency of amino acid replacement at residues S8, V10, I11, A15, V85, V133, N157, S163, V168, D174, R178, E182, and R188 in LTNPs was also seen in permuted datasets, implying that these are simply rapidly evolving residues. Permutation testing revealed that residues showing the greatest excess over expectation (A15, V85, N157, S163, V168, D174, R178, and R188) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions 9SVIG and 118QGYF among LTNPs. The regions V10 and 152KVEEA of nef were commonly deleted in LTNPs. However, permutation testing indicated that none of the regions displayed significantly excessive deletion in LTNPs. In conclusion, meta-analysis of HIV-1 nef sequences provides no clear evidence of whether defective nef sequences or particular regions of the protein play a significant role in disease progression.
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Broström, Christina, Anders Sönnerborg, Stefan Lindbäck, and Hans Gaines. "Low Relative Frequencies of CD26+CD4+ Cells in Long-Term Nonprogressing Human Immunodeficiency Virus Type 1-Infected Subjects." Clinical Diagnostic Laboratory Immunology 5, no. 5 (September 1, 1998): 662–66. http://dx.doi.org/10.1128/cdli.5.5.662-666.1998.
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ABSTRACT A broad antibody panel was used for immunophenotyping of human immunodeficiency virus type 1 (HIV-1)-infected patients who were long-term nonprogressors (LTNP). The LTNP were compared with patients in the early phase of infection and patients who had progressed to advanced immunodeficiency. Changes in CD8+ subset distribution were observed mainly at acquisition of HIV-1 infection, whereas CD4+ subset changes appeared during progression of HIV-1 infection. The decreasing levels of CD4+ cells were characterized by an increasing frequency of cells expressing the activation markers HLA-Dr and CD45RO but not the CD28 surface antigen. The LTNP exhibited significant changes compared to HIV-negative patients in almost all markers. Compared to patients in the early phase of infection, the only difference was a relatively lower frequency of CD4+ cells expressing CD26 among the LTNP. The results show that HIV-1-infected persons who have no signs of immunodeficiency despite many years of infection have an immunophenotypic pattern that is substantially different from that of noninfected persons. Despite the long duration of infection, the LTNP exhibit a pattern similar to that of newly infected persons, with the exception of lower expression of CD26 on CD4+ cells.
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Ogundeyi, MM, OO Oba-Daini, UP Adeniyi, and BI Adenuga. "A case report A Nigerian adolescent with Long term Non-progressive HIV-infection: A case report." Annals of Health Research 6, no. 2 (May 17, 2020): 239–45. http://dx.doi.org/10.30442/ahr.0602-13-86.
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Children infected with the Human Immunodeficiency Virus (HIV) can be rapid progressors or be at the end of the spectrum of the illness as Long-term Non-progressors (LTNPs). Long term non-progressors are patients who never received Highly Active Anti-Retroviral Therapy (HAART) during the first decade of life and are maintaining good CD4+ count associated with declining HIV RNA values. The literature on paediatric patients with LTNP infection is sparse.
An adolescent with HIV LTNP and likely vertical transmission of HIV is presented in this report. She presented with chronic cough, severe anaemia and dyspnea. She was wasted with bodyweight less than the 5th centile for age. She was not sexually active and had no history of blood transfusion, scarification, incisions or sharing of sharp grooming objects.
The results of investigations suggested pulmonary tuberculosis and HIV infection. Her CD4 count was 42%. She was commenced on HAART and subsequently, anti-tuberculosis medications according to NTBLCP/DOTS Programme with improvement in symptoms and appreciable weight gain.
Therefore routine voluntary HIV testing is recommended for all paediatric admission after consent or assent is obtained bearing in mind that a small subset of patients may fall into the LTNPs population.
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Crotti, Andrea, Francesca Neri, Davide Corti, Silvia Ghezzi, Silvia Heltai, Andreas Baur, Guido Poli, Elena Santagostino, and Elisa Vicenzi. "Nef Alleles from Human Immunodeficiency Virus Type 1-InfectedLong-Term-Nonprogressor Hemophiliacs with or without Late Disease Progression Are Defective in Enhancing Virus Replication and CD4 Down-Regulation." Journal of Virology 80, no. 21 (August 30, 2006): 10663–74. http://dx.doi.org/10.1128/jvi.02621-05.
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ABSTRACT Infection with human immunodeficiency virus (HIV)-encoding defective nef variants may contribute to a relatively benign course of disease in a minority of long-term nonprogressors (LTNP). We have examined the functions of nef alleles from six individuals belonging to the same cohort of hemophiliacs infected with HIV-1 prior to 1985 and classified as LTNP in 1995. Three out of six individuals have progressed to HIV disease (late progressors [LP]), whereas the three remainders have maintained their LTNP status at least up to 2003. The nef alleles were obtained from both plasma virus and peripheral blood mononuclear cells of all six individuals in 1995 and 1998. The proportion of sequences containing mutations not yielding Nef expression significantly diminished in 1998 versus that in 1995. Several previously defined functional regions of intact nef alleles were highly conserved. However, the major variant obtained in 1998 from plasma RNA of five out of six individuals significantly reduced HIV infectivity/replication and impaired Nef-mediated CD4 but not major histocompatibility complex class I antigen down-modulation from the cell surface. Thus, functional alterations of the nef gene are present in both LP and LTNP, suggesting that Nef defectiveness in vitro is not necessarily associated with the long-term maintenance of LTNP status. Of interest is the fact that isolates from three out of three LP showed a dual CCR5/CXCR4 coreceptor use (R5X4), in contrast to those from LTNP, which were exclusively R5. Thus, in vivo evolution of gp120 Env to CXCR4 use appears to be associated with HIV disease progression in individuals infected with nef-defective viruses.
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Gaardbo, Julie C., Hans J. Hartling, Jan Gerstoft, and Susanne D. Nielsen. "Thirty Years with HIV Infection—Nonprogression Is Still Puzzling: Lessons to Be Learned from Controllers and Long-Term Nonprogressors." AIDS Research and Treatment 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/161584.
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In the early days of the HIV epidemic, it was observed that a minority of the infected patients did not progress to AIDS or death and maintained stable CD4+ cell counts. As the technique for measuring viral load became available it was evident that some of these nonprogressors in addition to preserved CD4+ cell counts had very low or even undetectable viral replication. They were therefore termed controllers, while those with viral replication were termed long-term nonprogressors (LTNPs). Genetics and virology play a role in nonprogression, but does not provide a full explanation. Therefore, host differences in the immunological response have been proposed. Moreover, the immunological response can be divided into an immune homeostasis resistant to HIV and an immune response leading to viral control. Thus, non-progression in LTNP and controllers may be due to different immunological mechanisms. Understanding the lack of disease progression and the different interactions between HIV and the immune system could ideally teach us how to develop a functional cure for HIV infection. Here we review immunological features of controllers and LTNP, highlighting differences and clinical implications.
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Lefrère, Jean-Jacques, Laurence Morand-Joubert, Martine Mariotti, Hubertus Bludau, Béatrice Burghoffer, Jean-Claude Petit, and Françoise Roudot-Thoraval. "Even Individuals Considered as Long-Term Nonprogressors Show Biological Signs of Progression After 10 Years of Human Immunodeficiency Virus Infection." Blood 90, no. 3 (August 1, 1997): 1133–40. http://dx.doi.org/10.1182/blood.v90.3.1133.
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Abstract Despite a decade of human immunodeficiency virus (HIV) seropositivity, a few individuals termed as long-term nonprogressors (LTNPs) maintain a stable CD4+ T-cell count for a period of time. The aim of this study was to establish, through the sequential determination of all known predictors of HIV disease, the proportion of such patients having stringent criteria of true long-term nonprogression. Among 249 individuals who were HIV-infected and prospectively followed up over a 10-year period (1985 to 1995), 12 having a CD4+ T-cell count greater than 500/μL (LTNP I group) and 9 having a CD4+ T-cell count less than 500 but stable over time (LTNP II group) after at least 10 years of infection without intervention of antiviral therapy, were studied over the entire follow-up period. The plasma HIV RNA copy number and the serum concentrations of p24 antigen, each anti-HIV antibody, neopterin, β-2-microglobulin, Immunoglobulin (Ig) G and IgA were determined every 18 months over the study period. Cellular and plasma viremias were cross-sectionaly assayed in all 21 patients. Only two patients had strictly no marker of progression over the follow-up period. They were the only ones who had, over the 10-year period, a viral copy number too low to be detected. The other patients had a viral copy number higher than 400/mL at at least one visit and increasing over the follow-up period, and they evidenced one or more markers of virological or immunological deterioration. Cellular viremia was positive in all patients but two, while plasma viremia was negative in all but one. The population of individuals termed as LTNPs is not virologically and immunologically homogeneous. The majority present biological signs of HIV disease progression. A new pattern of true LTNP can be drawn through stringent criteria based on the whole known predictors. This pattern appears to be rare in HIV-positive population.
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Lefrère, Jean-Jacques, Laurence Morand-Joubert, Martine Mariotti, Hubertus Bludau, Béatrice Burghoffer, Jean-Claude Petit, and Françoise Roudot-Thoraval. "Even Individuals Considered as Long-Term Nonprogressors Show Biological Signs of Progression After 10 Years of Human Immunodeficiency Virus Infection." Blood 90, no. 3 (August 1, 1997): 1133–40. http://dx.doi.org/10.1182/blood.v90.3.1133.1133_1133_1140.
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Despite a decade of human immunodeficiency virus (HIV) seropositivity, a few individuals termed as long-term nonprogressors (LTNPs) maintain a stable CD4+ T-cell count for a period of time. The aim of this study was to establish, through the sequential determination of all known predictors of HIV disease, the proportion of such patients having stringent criteria of true long-term nonprogression. Among 249 individuals who were HIV-infected and prospectively followed up over a 10-year period (1985 to 1995), 12 having a CD4+ T-cell count greater than 500/μL (LTNP I group) and 9 having a CD4+ T-cell count less than 500 but stable over time (LTNP II group) after at least 10 years of infection without intervention of antiviral therapy, were studied over the entire follow-up period. The plasma HIV RNA copy number and the serum concentrations of p24 antigen, each anti-HIV antibody, neopterin, β-2-microglobulin, Immunoglobulin (Ig) G and IgA were determined every 18 months over the study period. Cellular and plasma viremias were cross-sectionaly assayed in all 21 patients. Only two patients had strictly no marker of progression over the follow-up period. They were the only ones who had, over the 10-year period, a viral copy number too low to be detected. The other patients had a viral copy number higher than 400/mL at at least one visit and increasing over the follow-up period, and they evidenced one or more markers of virological or immunological deterioration. Cellular viremia was positive in all patients but two, while plasma viremia was negative in all but one. The population of individuals termed as LTNPs is not virologically and immunologically homogeneous. The majority present biological signs of HIV disease progression. A new pattern of true LTNP can be drawn through stringent criteria based on the whole known predictors. This pattern appears to be rare in HIV-positive population.
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Jagannathan, Prasanna, Christine M. Osborne, Cassandra Royce, Maura M. Manion, John C. Tilton, Li Li, Steven Fischer, et al. "Comparisons of CD8+ T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness." Journal of Virology 83, no. 6 (January 7, 2009): 2728–42. http://dx.doi.org/10.1128/jvi.02128-08.
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ABSTRACT To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8+ T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8+ T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8+ T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8+ T cells were predominantly CD27+45RO+ for HIV and CD27−45RA+ for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8+ T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8+ T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8+ T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.
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Huang, Lei, Jianning Deng, Ren Lang, Guoyang Liao, and Wei Jiang. "Enriched LPS Staining within the Germinal Center of a Lymph Node from an HIV-Infected Long-Term Nonprogressor but Not from Progressors." Journal of Immunology Research 2020 (May 6, 2020): 1–5. http://dx.doi.org/10.1155/2020/7471380.
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An increased level of microbial translocation has been observed in HIV-infected individuals. The host response to microbial translocation is compromised in HIV-infected progressors but remains unknown in HIV-infected long-term nonprogressors (LTNPs). To evaluate microbial translocation in HIV, we assessed lipopolysaccharide (LPS) immunohistochemistry staining in lymph nodes. We found enriched bacterial LPS immunohistochemistry staining in the germinal center of a lymph node from an HIV-infected LTNP, evenly distributed from three progressors with impaired germinal center structures and rarely detected from two HIV-negative individuals. The impaired germinal center structures were consistent with collagen deposition in lymph nodes using immunohistochemistry staining. These results suggest greater immune responses against bacterial LPS translocation in LTNPs, which may reveal an important mechanism in controlling microbial translocation and disease progression in HIV LTNPs.
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Ciccosanti, Fabiola, Marco Corazzari, Rita Casetti, Alessandra Amendola, Diletta Collalto, Giulia Refolo, Alessandra Vergori, et al. "High Levels of TRIM5α Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors." Cells 10, no. 5 (May 14, 2021): 1207. http://dx.doi.org/10.3390/cells10051207.
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Autophagy is a lysosomal-dependent degradative mechanism essential in maintaining cellular homeostasis, but it is also considered an ancient form of innate eukaryotic fighting against invading microorganisms. Mounting evidence has shown that HIV-1 is a critical target of autophagy that plays a role in HIV-1 replication and disease progression. In a special subset of HIV-1-infected patients that spontaneously and durably maintain extremely low viral replication, namely, long-term nonprogressors (LTNP), the resistance to HIV-1-induced pathogenesis is accompanied, in vivo, by a significant increase in the autophagic activity in peripheral blood mononuclear cells. Recently, a new player in the battle of autophagy against HIV-1 has been identified, namely, tripartite motif protein 5α (TRIM5α). In vitro data demonstrated that TRIM5α directly recognizes HIV-1 and targets it for autophagic destruction, thus protecting cells against HIV-1 infection. In this paper, we analyzed the involvement of this factor in the control of HIV-1 infection through autophagy, in vivo, in LTNP. The results obtained showed significantly higher levels of TRIM5α expression in cells from LTNP with respect to HIV-1-infected normal progressor patients. Interestingly, the colocalization of TRIM5α and HIV-1 proteins in autophagic vacuoles in LTNP cells suggested the participation of TRIM5α in the autophagy containment of HIV-1 in LTNP. Altogether, our results point to a protective role of TRIM5α in the successful control of the chronic viral infection in HIV-1-controllers through the autophagy mechanism. In our opinion, these findings could be relevant in fighting against HIV-1 disease, because autophagy inducers might be employed in combination with antiretroviral drugs.
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Tasca, Karen Ingrid, Camila Renata Correa, Juliana Trindade Caleffi, Monica Banwart Mendes, Mariana Gatto, Vanessa Martinez Manfio, Caio Cavassan de Camargo, Francilene Capel Tavares, Mara Biasin, and Lenice do Rosário de Souza. "Asymptomatic HIV People Present Different Profiles of sCD14, sRAGE, DNA Damage, and Vitamins, according to the Use of cART and CD4+ T Cell Restoration." Journal of Immunology Research 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/7531718.
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We aimed to analyze markers of immune activation, inflammation, and oxidative stress in 92 asymptomatic HIV-infected patients according to the adequate (AR, >500 cells/mm3) or inadequate (IR, <500 cells/mm3) CD4+ T recovery and the presence or absence of antiretroviral treatment (cART). In relation to those newly diagnosed, they were divided into two groups, cART-naïve IR (nIR) and cART-naïve AR (nAR). Among those diagnosed more than five years ago, the following division was made: the cART-naïve long-term nonprogressors (LTNP); patient under cART and AR (tAR); and patients under cART and IR (tIR). We investigated the expression of soluble receptor for advanced glycation end products (sRAGE), high-mobility group-box protein −1 (HMGB1), soluble CD14 (sCD14), IL-8, IL-10, 8-isoprostane, vitamins, and DNA damage. We observed higher levels of sRAGE in tAR as compared to nIR, nAR, LTNP, and more sCD14 than in nIR and nAR. As for IL-10 levels, we found nIR > nAR > LTNP > tAR > tIR. Higher levels of 8-isoprostane were observed in nIR. LTNP presented a higher retinol dosage than tAR and less genotoxic damage induced by oxidative stress than the other groups. We suggest that the therapy, despite being related to lesser immune activation and inflammation, alters the vitamin profile and consequently increases the oxidative stress of patients. In addition, the lowest genotoxic index for LTNP indicates that both VL and cART could be responsible for the increased DNA damage. More studies are needed to understand the influence of cART on persistent immune activation and inflammation.
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Hadi, Kevin, Leah A. Walker, Debjani Guha, Ramachandran Murali, Simon C. Watkins, Patrick Tarwater, Alagarsamy Srinivasan, and Velpandi Ayyavoo. "Human immunodeficiency virus type 1 Vpr polymorphisms associated with progressor and nonprogressor individuals alter Vpr-associated functions." Journal of General Virology 95, no. 3 (March 1, 2014): 700–711. http://dx.doi.org/10.1099/vir.0.059576-0.
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Following infection with Human immunodeficiency virus 1 (HIV-1) there is a remarkable variation in virus replication and disease progression. Both host and viral factors have been implicated in the observed differences in disease status. Here, we focus on understanding the contribution of HIV-1 viral protein R (Vpr) by evaluating the disease-associated Vpr polymorphism and its biological functions from HIV-1 positive rapid progressor (RP) and long-term nonprogressor (LTNP) subjects. Results presented here show distinct variation in phenotypes of Vpr alleles from LTNP and RP subjects. Most notably, the polymorphism of Vpr at R36W and L68M associated with RP shows higher levels of oligomerization, and increased virus replication, whereas R77Q exhibits poor replication kinetics. Interestingly, we did not observe correlation with cell cycle arrest function. Together these results indicate that polymorphisms in Vpr in part may contribute to altered virus replication kinetics leading to the observed differences in disease progression in LTNP and RP groups.
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Rimawi, B. H., R. H. Rimawi, M. Micallef, L. Pinckney, S. L. Fowler, and T. C. Dixon. "Pediatric HIV Long-Term Nonprogressors." Case Reports in Infectious Diseases 2014 (2014): 1–3. http://dx.doi.org/10.1155/2014/752312.
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Patients infected with HIV are best categorized along a continuum from rapid progressors to HIV long-term nonprogressors. Long-term nonprogressors (LTNPs) are those in which AIDS develop many years after being infected with HIV, often beyond the 10-year mark, and represent 15–20% of the HIV infected patients. Many of these patients are able to control their infection and maintain undetectable viral loads for long periods of time without antiretroviral therapy. After a comprehensive literature search, we found extensive data related to HIV LTNPs in the adult population; however, very limited data was available related to LTNPs within the pediatric population. We present a case of pediatric HIV LTNPs, perinatally infected patient with undetectable viral loads, despite never receiving ART. Although there are not many instances of LTNPs among children, this child may be one, though she had intermittent viremia. She has continued to manifest serologic evidence of infection, with yearly ELISA and western blot positive tests. Based on the viral fitness studies that were performed, this case exemplifies an adolescent LTNP.
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Choudhary, Shailesh K., Neelima R. Choudhary, Katherine C. Kimbrell, Jonathan Colasanti, Argyrios Ziogas, David Kwa, Hanneke Schuitemaker, and David Camerini. "R5 Human Immunodeficiency Virus Type 1 Infection of Fetal Thymic Organ Culture Induces Cytokine and CCR5 Expression." Journal of Virology 79, no. 1 (January 1, 2005): 458–71. http://dx.doi.org/10.1128/jvi.79.1.458-471.2005.
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ABSTRACT Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4+ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4+ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5+ cells but also showed evidence of CPE on CCR5− cells. Furthermore, infection of FTOC by R5 HIV-1 induced IL-10 and transforming growth factor β (TGF-β) expression. Both IL-10 and TGF-β in turn induced CCR5 expression in FTOC. Induction of CCR5 expression via cytokine induction by R5 HIV-1 infection of CCR5+ thymocytes likely permitted further viral replication in newly CCR5+ thymocytes. CCR5 expression, therefore, is a key determinant of pathogenesis of R5 HIV-1 in FTOC.
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Migueles, Stephen A., Kristin A. Weeks, Eric Nou, Amy M. Berkley, Julia E. Rood, Christine M. Osborne, Claire W. Hallahan, et al. "Defective Human Immunodeficiency Virus-Specific CD8+ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy." Journal of Virology 83, no. 22 (September 2, 2009): 11876–89. http://dx.doi.org/10.1128/jvi.01153-09.
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ABSTRACT Identifying the functions of human immunodeficiency virus (HIV)-specific CD8+ T cells that are not merely modulated by the level of virus but clearly distinguish patients with immune control from those without such control is of paramount importance. Features of the HIV-specific CD8+ T-cell response in antiretroviral-treated patients (designated Rx <50) and untreated patients (long-term nonprogressors [LTNP]) matched for very low HIV RNA levels were comprehensively examined. The proliferative capacity of HIV-specific CD8+ T cells was not restored in Rx <50 to the level observed in LTNP, even though HIV-specific CD4+ T-cell proliferation in the two patient groups was comparable. This diminished HIV-specific CD8+ T-cell proliferation in Rx <50 was primarily due to a smaller fraction of antigen-specific cells recruited to divide and not to the numbers of divisions that proliferating cells had undergone. Exogenous interleukin-2 (IL-2) induced proliferating cells to divide further but did not rescue the majority of antigen-specific cells with defective proliferation. In addition, differences in HIV-specific CD8+ T-cell proliferation could not be attributed to differences in cellular subsets bearing a memory phenotype, IL-2 production, or PD-1 expression. Although polyfunctionality of HIV-specific CD8+ T cells in Rx <50 was not restored to the levels observed in LTNP despite prolonged suppression of HIV RNA levels, per-cell cytotoxic capacity was the functional feature that most clearly distinguished the cells of LTNP from those of Rx <50. Taken together, these data suggest that there are selective qualitative abnormalities within the HIV-specific CD8+ T-cell compartment that persist under conditions of low levels of antigen.
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Laurén, Anna, Rigmor Thorstensson, and Eva Maria Fenyö. "Comparative studies on mucosal and intravenous transmission of simian immunodeficiency virus (SIVsm): the kinetics of evolution to neutralization resistance are related to progression rate of disease." Journal of General Virology 87, no. 3 (March 1, 2006): 595–606. http://dx.doi.org/10.1099/vir.0.81409-0.
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The kinetics of appearance of autologous neutralizing antibodies were studied in cynomolgus macaques infected with simian immunodeficiency virus (SIVsm) by the intravenous (IV) route (six monkeys) or the intrarectal (IR) route (ten monkeys). The SIVsm inoculum virus and reisolates obtained at 2 weeks, 3 or 4 months and later than 1 year were tested in a GHOST(3) cell line-based plaque-reduction assay with autologous sera collected at the same sampling times. All monkeys developed a neutralizing-antibody response to the inoculum virus, those infected by the IV route earlier than monkeys infected by the IR route. Animals were divided into progressor (P), slow-progressor (SP) and long-term non-progressor (LTNP) monkeys, based on progression rate. In P monkeys, neutralization escape could be demonstrated by 3 months post-infection. Neutralization-resistant variants also emerged in SP and LTNP monkeys, but were much delayed compared with P monkeys. Evolution of neutralization resistance was also demonstrated by a positive-control serum in the heterologous reaction. Pooled sera from four LTNP monkeys showed a broad neutralizing capacity, including neutralization of escape variants. These results from a large group of infected monkeys showed that SIV evolves to neutralization resistance in the infected host and that the kinetics of this evolution are related to the route of transmission and the progression rate of SIV disease. The results suggest an important role for neutralizing antibodies in controlling viraemia. Although this control is transient in the infected host, neutralization resistance is relative and variant viruses may be neutralized by a broadly cross-neutralizing serum pool.
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Ling, Binhua, Stefanie Perez, Ann-Marie Johnson, and lara Doyle-Meyers. "Immune restoration, activation and viral reservoirs in gut-associated lymphoid tissue in SIV-infected long-term nonprogressing Chinese rhesus macaques on antiretroviral therapy (VIR1P.1130)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 74.7. http://dx.doi.org/10.4049/jimmunol.194.supp.74.7.
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Abstract HIV infected long-term nonprogressors (LTNPs) and elite controllers (ECs) maintain enduring control of HIV infection without antiretroviral therapy. However, persistent tissue reservoirs and chronic inflammation still exist. We previously found that 1/3 of SIV-infected Chinese rhesus macaques mimics HIV-infected LTNPs/ECs. Here we studied whether therapy can further decrease tissue reservoirs, restore immune function and decrease inflammation in this model. Six LTNPs/ECs and 4 progressors were treated with PMPA and FTC daily for up to 24 weeks during chronic infection. Blood, lymph nodes and gut tissues were collected. Cell-associated viral DNA levels from purified CD4+ T cells in blood and gut lymphocytes were quantified by real-time PCR. The size of reservoirs was evaluated by quantitative coculture assays and real-time PCR. Immune cells restoration including IL-17+ subsets, proliferation and immune activation were monitored by flow cytometry. We found that plasma viral loads in all animals were suppressed and maintained to undetectable throughout ART. The levels of IL-17 expression in CD4 and CD8 T cells were not fully restored but slightly increased after ART. Immune activation significantly decreased. In conclusion, the ChRM nonhuman primate model is excellent for testing novel therapeutic interventions on TP and LTNPs/ECs for HIV eradication. Initiation of ART may be necessary for improvement of immune function for HIV/SIV infected LTNP/ECs.
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Keckler, M. Shannon, Vida L. Hodara, Laura M. Parodi, and Luis D. Giavedoni. "Maintenance or Emergence of Chronic Phase Secondary Cytotoxic T Lymphocyte Responses after Loss of Acute Phase Immunodominant Responses Does Not Protect SIV-Infected Rhesus Macaques from Disease Progression." Journal of Biomedicine and Biotechnology 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/279391.
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The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood. In this paper, we document the cytotoxic T lymphocyte (CTL) response to SIV and its effects on viral evolution in an effort to identify events associated with disease progression regardless of MHC allele expression. We observed the evolution of epitopes targeted by CTLs in a group of macaques that included long-term nonprogressing (LTNP), slowly progressing (SP), normally progressing (NP), and rapidly progressing (RP) animals. Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses. These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.
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Scala, E., G. D'Offizi, R. Rosso, O. Turriziani, R. Ferrara, A. M. Mazzone, G. Antonelli, F. Aiuti, and R. Paganelli. "C-C chemokines, IL-16, and soluble antiviral factor activity are increased in cloned T cells from subjects with long-term nonprogressive HIV infection." Journal of Immunology 158, no. 9 (May 1, 1997): 4485–92. http://dx.doi.org/10.4049/jimmunol.158.9.4485.
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Abstract A combination of three beta, or C-C, chemokines, as well as IL-16, have been shown to inhibit HIV replication in vitro. Cellular antiviral factor is a more potent agent, and acts on all HIV strains. All are mainly, but not exclusively, produced by CD8+ T cells, both in HIV+ and healthy subjects. We studied the production of these HIV-suppressive factors in patients with HIV infection at different stages of disease. No difference in production by PBMC stimulated with PHA has been observed in asymptomatic HIV+, long-term nonprogressors (LTnP), and AIDS patients. When T cell line supernatants from these three groups were studied, no significant difference was found for C-C chemokines or IL-16 production, and viral suppression. However, T cell clones from LTnP secreted higher levels of all three chemokines, IL-16, and exerted a stronger inhibition on HIV replication. CD8+ clones showed a higher production than CD4+ clones. These clones were able to produce all antiviral factors irrespective of the secretion of type 1 or type 2 cytokines. The antiviral activities were not correlated, implying that viral suppression did not depend solely on C-C chemokines or IL-16. We postulate that all factors are needed to prevent HIV disease progression.
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Cabrera-Rodríguez, Romina, Silvia Pérez-Yanes, Rafaela Montelongo, José M. Lorenzo-Salazar, Judith Estévez-Herrera, Jonay García-Luis, Antonio Íñigo-Campos, et al. "Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6." International Journal of Molecular Sciences 23, no. 11 (May 31, 2022): 6180. http://dx.doi.org/10.3390/ijms23116180.
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The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.
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Ushkov, Valentin, Ruslan Ibragimov, Oleg Figovsky, and Svetlana Samchenko. "REPAIR MORTARS OBTAINED BY PLASMA MODIFICATION AND VORTEX ACTIVATION." Architecture and Engineering 7, no. 4 (December 29, 2022): 60–69. http://dx.doi.org/10.23968/2500-0055-2022-7-4-60-69.
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Introduction: The service life of reinforced-concrete structures can be increased with the use of effective repair compositions obtained by activating the original components. Purpose of the study: We aimed to develop effective repair compounds obtained by activating the original components. Methods: To process the original components, low-temperature non-equilibrium plasma (LTNP) and electromagnetic activation in a vortex layer device were used. In the course of the study, we used polypropylene, steel, glass, and basalt fiber and fiber made of structured ferromagnetic microwire. Electron microscopy and X-ray diffraction analysis were applied. Results: It was established that the combined use of the above methods for the modification of raw components makes it possible to improve the strength of these materials by more than 50%, which is due to the characteristics of structure formation in the developed compositions. For instance, LTNP increases the amount of portlandite and reduces the main phases of cement stone— C3S and β-C2S, and vortex activation contributes to an increase in the total number of crystalline phases. Quartz powder particles processed in an electromagnetic mill are characterized by layered structure, high surface roughness, large developed cracking, as well as inclusions as a result of impact action. All that improves the physical and mechanical properties of the resulting repair compositions by an average of 20%. Repair compositions additionally treated with plasma modification feature new hydrated formations on quartz grains.
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van Gils, Marit J., Evelien M. Bunnik, Judith A. Burger, Yodit Jacob, Becky Schweighardt, Terri Wrin, and Hanneke Schuitemaker. "Rapid Escape from Preserved Cross-Reactive Neutralizing Humoral Immunity without Loss of Viral Fitness in HIV-1-Infected Progressors and Long-Term Nonprogressors." Journal of Virology 84, no. 7 (January 13, 2010): 3576–85. http://dx.doi.org/10.1128/jvi.02622-09.
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ABSTRACT A substantial proportion of human immunodeficiency virus type 1 (HIV-1)-infected individuals has cross-reactive neutralizing activity in serum, with a similar prevalence in progressors and long-term nonprogressors (LTNP). We studied whether disease progression in the face of cross-reactive neutralizing serum activity is due to fading neutralizing humoral immunity over time or to viral escape. In three LTNP and three progressors, high-titer cross-reactive HIV-1-specific neutralizing activity in serum against a multiclade pseudovirus panel was preserved during the entire clinical course of infection, even after AIDS diagnosis in progressors. However, while early HIV-1 variants from all six individuals could be neutralized by autologous serum, the autologous neutralizing activity declined during chronic infection. This could be attributed to viral escape and the apparent inability of the host to elicit neutralizing antibodies to the newly emerging viral escape variants. Escape from autologous neutralizing activity was not associated with a reduction in the viral replication rate in vitro. Escape from autologous serum with cross-reactive neutralizing activity coincided with an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites in the viral envelope. Positive selection pressure was observed in the variable regions in envelope, suggesting that, at least in these individuals, these regions are targeted by humoral immunity with cross-reactive potential. Our results may imply that the ability of HIV-1 to rapidly escape cross-reactive autologous neutralizing antibody responses without the loss of viral fitness is the underlying explanation for the absent effect of potent cross-reactive neutralizing humoral immunity on the clinical course of infection.
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Tolstrup, Martin, Alex L. Laursen, Jan Gerstoft, Finn S. Pedersen, Lars Ostergaard, and Mogens Duch. "Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression." Sexual Health 3, no. 4 (2006): 281. http://dx.doi.org/10.1071/sh06002.
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Background: The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. Methods: The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. Results: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. Conclusion: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337–45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.
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Tilton, John C., Marlise R. Luskin, Alison J. Johnson, Maura Manion, Claire W. Hallahan, Julia A. Metcalf, Mary McLaughlin, Richard T. Davey, and Mark Connors. "Changes in Paracrine Interleukin-2 Requirement, CCR7 Expression, Frequency, and Cytokine Secretion of Human Immunodeficiency Virus-Specific CD4+ T Cells Are a Consequence of Antigen Load." Journal of Virology 81, no. 6 (December 20, 2006): 2713–25. http://dx.doi.org/10.1128/jvi.01830-06.
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ABSTRACT Virus-specific CD4+ T-cell responses are thought to be required for the induction and maintenance of many effective CD8+ T-cell and B-cell immune responses in experimental animals and humans. Although the presence of human immunodeficiency virus (HIV)-specific CD4+ T cells has been documented in patients at all stages of HIV infection, many fundamental questions regarding their frequency and function remain. A 10-color, 12-parameter flow cytometric panel was utilized to examine the frequency, memory phenotype (CD27, CCR7, and CD45RA), and cytokine production (interleukin-2 [IL-2], gamma interferon, and tumor necrosis factor alpha) of CD4+ T cells specific for HIV antigens as well as for adenovirus, Epstein-Barr virus (EBV), influenza H1N1 virus, influenza H3N2 virus, cytomegalovirus, varicella-zoster virus (VZV), and tetanus toxoid in normal controls, long-term nonprogressors (LTNP), and HIV-infected patients with progressive disease on or off therapy. The HIV-specific CD4+ T-cell responses in LTNP and patients on therapy were similar in frequency, phenotype, and cytokine production to responses directed against adenovirus, EBV, influenza virus, and VZV. HIV-specific CD4+ T cells from patients off antiretroviral therapy demonstrated a shift towards a CCR7− CD45RA− phenotype and a reduced percentage of IL-2-producing cells. The alterations in cytokine production during HIV viremia were found to be intrinsic to the HIV-specific CD4+ T cells and caused a requirement for IL-2 supplied exogenously for proliferation to occur. These observations suggest that many previously described changes in HIV-specific CD4+ T-cell function and phenotype are a consequence of high levels of antigen in viremic patients. In addition, defects in function and phenotype of HIV-specific CD4+ T cells are not readily discernible in the context of antiretroviral therapy but rather are similar to responses to other viruses.
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Williams, R. Michael, Joaquin Zuniga, Julio Granados, and Edmond J. Yunis. "Role of natural killer cell activity in HIV infections, aging, and breast cancer survival." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 120.5. http://dx.doi.org/10.4049/jimmunol.202.supp.120.5.
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Abstract Natural killer cell activity participates in the elimination of tumors and virus infections. Data presented here include their role in a virus infection (HIV), metastatic breast cancer, and aging per se. We have analyzed two gene segments MHC HLA class I ligands and NK receptors Each have single amino acid differences. Together these alleles can identify long term survivors. Homozygosity of HLA–Bw4 supertype in HIV progression has been described. Since HLA-KIR genetic interactions of HLA-Bw4 with KIR (3DS1) only included Bw4, with the exception of B*27 and B*44 that use different mechanism of protection, on the clinical outcome of HIV infection, NK–ligand interactions (NKG2A-HLA-E with HLA class I leader peptides) explain the long term non-progressors (LTNP) to AIDS. HLA-B alleles have Methionine (Met) or Threonine (Thr) at second position (P2) of their leader peptide. HLA-Bw4 alleles, with exception of B*38, encode leader peptide with Thr at P2 and HLA-Bw6 genes that encode Met at P2 are B*07, B*08 and B*14. All others have Thr at P2. Comparisons of the Thr in LTNP with progressors, up to 15 years. with non-infected Caucasian controls were significant. Also, aged Mexicans demonstrated significant increase of homozygosity of Thr at P2 and Mexican patients with metastatic breast cancer were studied 10 years after treatment with surgery and chemotherapy, The 39 survivors demonstrated significant increase of homozygosity of Thr at P2 compared to controls without cancer and the 37 non survivors. These findings need to be studied in different malignancies and different ethnicities as well as in mouse models. Our findings support the immunogenetic theory of cancer and aging.
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Pernas, Maria, Victor Sanchez-Merino, Concepcion Casado, Alberto Merino-Mansilla, Isabel Olivares, Eloisa Yuste, and Cecilio Lopez-Galindez. "HIV-1 Dual Infected LTNP-EC Patients Developed an Unexpected Antibody Cross-Neutralizing Activity." PLOS ONE 10, no. 8 (August 10, 2015): e0134054. http://dx.doi.org/10.1371/journal.pone.0134054.
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Antoni, Sascha, Nicole Walz, Margot Landersz, Michael Humbert, Christian Seidl, Matthias T. Dittmar, and Ursula Dietrich. "Genetic and Biological Characterization of Recombinant HIV Type 1 with Env Derived from Long-Term Nonprogressor (LTNP) Viruses." AIDS Research and Human Retroviruses 23, no. 11 (November 2007): 1377–86. http://dx.doi.org/10.1089/aid.2007.0113.
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Baron, Sarah, Meghan Garrett, and Mark D. Hicar. "1008. Presence of Antibody Dependent Cell Cytotoxicity (ADCC) Functional Antibodies that Target a Complex Gp41 Epitope Correlates with Long-term Non-progression and ADCC is Maintained with Mutants Using Germline Heavy Chain Variable Gene Sequence of VH1-02 Gene." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S594—S595. http://dx.doi.org/10.1093/ofid/ofab466.1202.
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Abstract Background Recent data supports that improved qualitative antibody responses correlate with elite controllers (EC) of HIV. As ADCC has been associated with protection in vaccine studies, thorough exploration of antibodies that facilitate ADCC is warranted. In studies on monoclonal antibodies from long-term non-progressors (LTNPs), our laboratory has previously described highly mutated antibodies against a complex conformational epitope with contributions from both gp41 heptad repeat regions. Despite using the VH1-02 gene segment, known to contribute to some of the broadest neutralizing antibodies against HIV, members of these antibodies, termed group 76C antibodies, did not exhibit broad neutralization. Methods Our goal was to characterize the non-neutralizing functions of antibodies of group 76C, to assess targeting of the epitope in various clinical presentations, and to assess the development of these antibodies by comparison to their predicted common ancestor. Serum samples were obtained from HIV+ clinical groups: EC, LTNP, stable CD4 counts on therapy, and those off therapy. Results In antibody/serum competition assays, comparison to VRC01 which also uses VH1-02, showed that antibodies targeting the 76C group epitope were enriched in LTNPs. We then show recombinant antibodies of 76C members 6F5 and 6F11 both have robust ADCC activity, despite their sequence disparity. Sequence analysis predicted the common ancestor of this clonal group would utilize the germline non-mutated variable gene. We produced a recombinant ancestor Ab (76Canc) with a heavy chain utilizing the germline variable gene sequence paired to the 6F5 light chain. 76Canc binds HIV envelope constructs near the original group C epitope. 76Canc also shows comparable ADCC to 6F5 and 6F11 on both clade B and C constructs. Common ancestor antibodies maintain function and these types of antibodies correlate to a non-progressive clinical state. (A) Serum from long-term non-progressors (LTNPs) compared to serum from a group of HIV infected with lower CD4 levels as a control for viral load were used to compete against biotinylated CD4 binding site (VRC01) and 76C Gp41 conformational epitope (6F11) targeting antibodies. Serum dilutions were chosen to align means near 50%. Means with 95% confidence intervals are shown. (B) Monoclonal antibody 76Canc was created using the germline sequence of the heavy chain variable region with the CDR3 and light chain of 76C member. Antibody dependent cell cytotoxicity flow cytometric based assays were performed using gp41 proteins from clade B (MN) and clade C (ZA1197). Conclusion Certain antibodies present early on in infection may contribute to overall clinical course. Variable gene germline sequences that support functional activity against HIV could be targeted in vaccine regimens. Disclosures All Authors: No reported disclosures
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Narayanan, Vaasudev, and Bhargav Parsi. "Center Symmetric Local Descriptors for Image Classification." International Journal of Natural Computing Research 7, no. 4 (October 2018): 56–70. http://dx.doi.org/10.4018/ijncr.2018100104.
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Local feature description forms an integral part of texture classification, image recognition, and face recognition. In this paper, the authors propose Center Symmetric Local Ternary Mapped Patterns (CS-LTMP) and eXtended Center Symmetric Local Ternary Mapped Patterns (XCS-LTMP) for local description of images. They combine the strengths of Center Symmetric Local Ternary Pattern (CS-LTP) which uses ternary codes and Center Symmetric Local Mapped Pattern (CS-LMP) which captures the nuances between images to make the CS-LTMP. Similarly, the auhtors combined CS-LTP and eXtended Center Symmetric Local Mapped Pattern (XCS-LMP) to form eXtended Center Symmetric Local Ternary Mapped Pattern (XCS-LTMP). They have conducted their experiments on the CIFAR10 dataset and show that their proposed methods perform significantly better than their direct competitors.
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OLOFSSON, Anders, Ulf HELLMAN, Peter TEN DIJKE, Susanne GRIMSBY, Hidenori ICHIJO, Anita MORÉN, Kohei MIYAZONO, and Carl-Henrik HELDIN. "Latent transforming growth factor-β complex in Chinese hamster ovary cells contains the multifunctional cysteine-rich fibroblast growth factor receptor, also termed E-selectin-ligand or MG-160." Biochemical Journal 324, no. 2 (June 1, 1997): 427–34. http://dx.doi.org/10.1042/bj3240427.
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Transforming growth factor-β (TGF-β) is secreted as latent high molecular mass complexes from producer cells. The N-terminal precursor remnant, also called latency-associated peptide (LAP), forms a non-covalently linked complex with TGF-β and confers the latency to TGF-β. In human platelets and certain other cell types, latent TGF-β binding protein-1 (LTBP-1) is disulphide-linked to LAP, and forms complexes of more than 230 kDa. In addition, LTBP-2 and -3, which are structurally similar to LTBP-1, can be part of latent TGF-β complexes. In Chinese hamster ovary (CHO) cells transfected with the TGF-β1 cDNA, a major part of the latent TGF-β secreted into the medium is a 100-kDa small latent complex containing TGF-β and LAP. In addition, we found two other forms of latent TGF-β complexes, i.e. a 220-kDa complex containing LTBP-1, and a 220-kDa complex containing a 140-kDa protein. Purification of the 140-kDa component, termed latent TGF-β complexed protein-1 (LTCP-1), followed by amino acid sequencing and cDNA cloning from a CHO cell cDNA library, revealed that it is a hamster counterpart of a previously identified, multifunctional protein known as chicken cysteine-rich fibroblast growth factor (FGF) receptor, mouse E-selectin-ligand and rat MG-160 (a 160-kDa membrane sialoglycoprotein of the Golgi apparatus). Immunoprecipitation of LTCP-1 and TGF-β1 from CHO cells stably transfected with TGF-β1 precursor cDNA revealed that the expressed protein forms a complex with LAP, and that a major part of the complex is secreted. Northern blot analysis showed that mRNA for LTCP-1 was expressed in large amounts in testis, ovary and placenta, but less abundantly in other tissues. These results suggest that TGF-β, produced in certain cell types, may form a complex with LTCP-1, which may have different properties compared with other latent TGF-β complexes. It remains to be investigated whether the complex formation between LTCP-1 and TGF-β1 also occurs in other cells, whether the association between them occurs in the Golgi complex, and whether it affects the interaction of LTCP-1 with FGF or E-selectin.
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Corder, Elizabeth, Luciano Galeazzi, Claudio Franceschi, Andrea Cossarizza, Roberto Paganelli, Marcello Pinti, Cristina Mussini, et al. "Differential course of HIV-1 infection and apolipoprotein E polymorphism." Open Medicine 2, no. 4 (December 1, 2007): 404–16. http://dx.doi.org/10.2478/s11536-007-0039-x.
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AbstractWe studied the course of infection with human immunodeficiency virus type 1 (HIV-1) in relation to apolipoprotein E (APOE) polymorphism found for 209 Italians treated at Infectious Disease Clinics in Rome and Modena. Clinically, patients were classified into four groups according to the yearly rate of decline in CD4+ cell count (LTNP: long-term non-progression; SLOW, ’NORMAL’ or RAPID). Patients at both extremes of the clinical spectrum, i.e. those who rapidly progressed to AIDS and those with stable high CD4 cell counts, had few APOE ɛ4 and ɛ2 alleles (P = 0.04). Detailed clinical information was then used to construct four model-based clinical profiles using grade-of-membership analysis (GoM), predictive of APOE genotypic frequencies: 1. The clinical profile associated with good long-term prognosis lacked ɛ2 (P=0.01); 2. Disease progression to AIDS was associated with ɛ4 and ɛ2, most evident for zidovudine-lamivudine regimens without a protease inhibitor (P = 0.03); and, 3. AIDS patients had low ɛ4 and ɛ2 frequencies, consistent with a high mortality rate among ɛ4+ and ɛ2+ AIDS patients. These findings suggest allele-specific immunomodulatory effects involving inherited APOE isoform important enough to alter the clinical course of HIV infection and, possibly, drug efficacy. They imply a connection between lipid metabolism and immunity potentially relevant to common disorders.
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Pernas, María, Concepción Casado, Carolina Arcones, Anuska Llano, Víctor Sánchez-Merino, Beatriz Mothe, José L. Vicario, et al. "Low-Replicating Viruses and Strong Anti-Viral Immune Response Associated with Prolonged Disease Control in a Superinfected HIV-1 LTNP Elite Controller." PLoS ONE 7, no. 2 (February 24, 2012): e31928. http://dx.doi.org/10.1371/journal.pone.0031928.
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Ahmad, Ali, Suzanne Samarani, Ayoub Abulkhir, and Devendra Amre. "Regulation of IL-37 and its signaling co-receptor IL-1R8 in HIV infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 75.14. http://dx.doi.org/10.4049/jimmunol.202.supp.75.14.
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Abstract IL-37 is a member of the IL-1 family with potent anti-inflammatory and immune deviating effects. The cytokine exerts its biological effects via IL-1R8 (also formerly known as TIR-8 and SIGIRR), the signaling component of its receptor. Little is known about the regulation of the cytokine and of its receptor in HIV infection. The objective of this study was to investigate how the production of the cytokine and the expression of the signalling component of its receptor on immune cells was regulated in HIV infection. The study was conducted using biological samples from a cross section of HIV-infected individuals. Concentrations of the cytokine and soluble (shed) IL-1R8 in serum samples were determined by ELISA. The expression of IL-1R8 on immune cells was determined by flow cytometry. The effects of exogenous IL-37 on HIV replication in human PHA blasts were determined in in vitro assays. We found that the cytokine concentrations tended to decrease in treatment-naïve HIV-infected individuals compared with the ART-treated patients. Higher concentrations of the cytokine were observed in sera from LTNP. The transcripts for the most complete isoform of the cytokine, b, disappeared from the patients’ PBMC. The expression of IL-1R8 on immune cells was decreased in HIV-infected individuals. On the other hand, concentrations of its soluble form increased in the sera from the virus-infected individuals. The trend was reversed in the patients undergoing anti-retroviral treatment. Soluble IL-1R8 attenuated anti-inflammatory effects of the cytokine. Collectively, these results suggest that the IL-37/IL-1R8 axis is functionally compromised in HIV-infected individuals.
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Kang, Seok, Ha-Mok Jeong, Beom-Suk Kim, and Joon-Shik Yoon. "Risk Analysis of Needle Injury to the Long Thoracic Nerve during Ultrasound-Guided C7 Selective Nerve Root Block." Medicina 57, no. 6 (June 19, 2021): 635. http://dx.doi.org/10.3390/medicina57060635.
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Background and Objectives: Ultrasound (US)-guided cervical selective nerve root block (SNRB) is a widely used treatment for upper limb radicular pain. The long thoracic nerve (LTN) passes through the middle scalene muscle (MSM) at the C7 level. The needle trajectory of US-guided C7 SNRB pierces the MSM, therefore indicating a high probability of injury to the LTN. We aimed to identify the LTN and to investigate the risk of needle injury to the nerve during US-guided C7 SNRB. Materials and Methods: This retrospective observational study included 30 patients who underwent US-guided SNRB at the C7 level in a university hospital. We measured the maximal cross-sectional diameter (MCSD) of the LTN and cross-sectional area (CSA) of the C7 nerve root and assessed the injury risk of LTN during US-guided C7 SNRB by simulating the trajectory of the needle in the ultrasound image. Results: The LTN was detectable in all the cases, located inside and outside the MSM in 19 (63.3%) and 11 (36.7%) of cases, respectively. The LTN’s mean MCSD was 2.10 mm (SD 0.13), and the C7 root’s CSA was 10.78 mm2 (SD 1.05). The LTN location was within the simulated risk zone in 86.7% (26/30) of cases. Conclusion: Our findings suggest a high potential for LTN injury during US-guided C7 SNRB. The clear visualization of LTNs in the US images implies that US guidance may help avoid nerve damage and make the procedure safer. When performing US-guided C7 SNRB, physicians should take into consideration the location of the LTN.
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Kalyadin, Anton Yu, Grigor V. Nalbandyan, Vadim G. Soloviev, Anfisa A. Bogdanova, and Valentin A. Ushkov. "Plasma modification of construction mortar components, an efficient method of increasing their performance." Vestnik MGSU, no. 5 (May 2019): 548–58. http://dx.doi.org/10.22227/1997-0935.2019.5.548-558.
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Introduction. The article considers the enhancement of physical and mechanical parameters of construction mortars used for recovering and repairing of building structures of communication collectors by using low-temperature nonequilibrium plasma. The study vindicated the expediency of treatment of construction mortar raw materials with LTNP to enhance their physical and mechanical parameters. The effect of plasma modification of raw materials on Portland cement phase composition, granulometric composition of the sand and mortar properties are analysed. The influence of multiplicity of silica sand and mixing water plasma treatment on the construction mortar strength is considered.
Materials and methods. Cement-sand mortars are obtained from Portland cement of the CEM I 32.5N and CEM I 42.5N brands and silica sand with the fineness moduli of Mf = 0.32 and Mf = 0.63 and a separate fraction of less than 0.16 mm. Setting time and strength of the building mortars are defined according to GOST state standards in effect. Granulometric composition of the cement is explored by means of Analysette-22 particle size microanalyser, while ARL Optim’X spectrometer is used for studying phase composition of the cement stone, silica sand and cement-sand mortars.
Results. It is determined that the plasma treatment of Portland cement reduces the grout normal consistency by 15 to 17 % and decreases its setting time by a factor of 3 to 4. Treatment of mixing water with the nonequilibrium low-temperature plasma removes its hardness, forming additional crystallization nuclei. The plasma-treated mixing water increases the curing rate of cement-sand mortars up to 50 % at the early stages of hardening and up to 30 % on the 28th day of hardening. Using plasma-treated silica sand decreases size of its particles and results in partial transition of the crystalline structure into the amorphous one. This reduces water demand of the sand by 10 to 18 %.
Conclusions. The expedience of plasma treatment of raw materials to enhance the physical and mechanical properties of mortars is vindicated. Owing to the plasma modification of raw materials, quality and process characteristics of construction mortars are improved. The presented method of the plasma treatment of raw materials used to prepare the construction mortars is characterized with high degree of efficiency and convenience of application.
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Gozlan, H., R. Khazipov, D. Diabira, and Y. Ben-Ari. "In CA1 hippocampal neurons, the redox state of NMDA receptors determines LTP expressed by NMDA but not by AMPA receptors." Journal of Neurophysiology 73, no. 6 (June 1, 1995): 2612–17. http://dx.doi.org/10.1152/jn.1995.73.6.2612.
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1. Using extracellular recording techniques in the CA1 region of the rat hippocampus, we have evaluated the effects of the redox reagents 5,5O-dithiobis-2-nitrobenzoic acid (DTNB) and tris (carboxyethyl) phosphine (TCEP) on long-term potentiation (LTP) expressed by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. In physiological conditions a high-frequency stimulation (HFS) of Schaffer collateral-commissural fibers induced a LTP expressed by a persistent increase (73 +/- 13%, mean +/- SE, n = 8/10) of AMPA field potentials (LTPA). In the presence of 10 microM of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and reduced concentration of Mg2+ (0.1 mM) to boost NMDA receptors, the HFS induced LTP of NMDA field potentials (LTPN; 62 +/- 11%, n = 8/10). 2. The thiol-oxidizing reagent DTNB (200 microM) reduced, by 46 +/- 5% (n = 24), NMDA-receptor field potentials (NMDA-FP), and this effect could not be reversed by extensive washing. The disulfide-reducing agent TCEP (200 microM) slightly increased AMPA-FP and reversed the DTNB-induced inhibition of NMDA-FP. 3. DTNB (200 microM, 10 min), and TCEP (200 microM, 20 min), had no effect on AMPA-FP (98 +/- 3% and 101 +/- 5%, respectively, n = 12). 4. DTNB (200 microM, 15 min) did not prevent the induction or expression of LTPA (-12 and -5%, respectively, n = 8/8). Similar results were observed with TCEP (200 microM, 20 min).(ABSTRACT TRUNCATED AT 250 WORDS)
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Hassan, H. F., A. S. Al-Nuaimi, R. Taha, and T. M. A. Jafar. "Development of Asphalt Pavement Temperature Models for Oman." Journal of Engineering Research [TJER] 2, no. 1 (December 1, 2005): 32. http://dx.doi.org/10.24200/tjer.vol2iss1pp32-42.
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Asphalt pavements form an integral part of any transportation system. The structural capacity of the hot mix asphalt concrete layers depends on many factors including its temperature. Moreover, temperature can be a major contributor to several types of distresses. Therefore, temperature is a significant factor that affects the performance and life span of a pavement. The Sultanate of Oman's road network expanded at a phenomenal pace from approximately 10 km of paved roads in 1970 to 9,673 km in 2001. with the recent SHRP and LTTP research findings, it was necessary to investigate the applicability of the models developed from these research studies to Oman's environmental conditions and more generally to the Arabian Gulf climate. This paper presents the research undertaken to develop models to predict high and low asphalt pavement temperatures in Oman. A pavement monitoring station was set-up at the Sultan Qaboos University (SQU) campus to monitor air, pavement temperatures and solar radiation. Data were collected for 445 days. Daily minimum and maximum temperatures were recorded. A regression analysis was used to develop the low pavement temperature model. A stepwise regression was used to develop high temperature models using air temperature, solar radiation, and duration of solar radiation as independent variables. The developed models were compared with the SHRP and LTPP models. The SHRP and LTPP models were found to be more conservative than the developed models, which are more suitable for predicting pavement temperatures in Oman, and more generally in the Gulf region.
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Bhandarkar, Sumitha, Saurabh Jain, and A. L. Narasimha Reddy. "LTCP." ACM SIGCOMM Computer Communication Review 36, no. 1 (January 10, 2006): 41–50. http://dx.doi.org/10.1145/1111322.1111332.
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Nunes, Irene, Pierre-Emmanuel Gleizes, Christine N. Metz, and Daniel B. Rifkin. "Latent Transforming Growth Factor-β Binding Protein Domains Involved in Activation and Transglutaminase-dependent Cross-Linking of Latent Transforming Growth Factor-β." Journal of Cell Biology 136, no. 5 (March 10, 1997): 1151–63. http://dx.doi.org/10.1083/jcb.136.5.1151.
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Transforming growth factor-β (TGF-β) is secreted by many cell types as part of a large latent complex composed of three subunits: TGF-β, the TGF-β propeptide, and the latent TGF-β binding protein (LTBP). To interact with its cell surface receptors, TGF-β must be released from the latent complex by disrupting noncovalent interactions between mature TGF-β and its propeptide. Previously, we identified LTBP-1 and transglutaminase, a cross-linking enzyme, as reactants involved in the formation of TGF-β. In this study, we demonstrate that LTBP-1 and large latent complex are substrates for transglutaminase. Furthermore, we show that the covalent association between LTBP-1 and the extracellular matrix is transglutaminase dependent, as little LTBP-1 is recovered from matrix digests prepared from cultures treated with transglutaminase inhibitors. Three polyclonal antisera to glutathione S–transferase fusion proteins containing amino, middle, or carboxyl regions of LTBP-1S were used to identify domains of LTBP-1 involved in crosslinking and formation of TGF-β by transglutaminase. Antibodies to the amino and carboxyl regions of LTBP-1S abrogate TGF-β generation by vascular cell cocultures or macrophages. However, only antibodies to the amino-terminal region of LTBP-1 block transglutaminase-dependent cross-linking of large latent complex or LTBP-1. To further identify transglutaminase-reactive domains within the amino-terminal region of LTBP-1S, mutants of LTBP-1S with deletions of either the amino-terminal 293 (ΔN293) or 441 (ΔN441) amino acids were expressed transiently in CHO cells. Analysis of the LTBP-1S content in matrices of transfected CHO cultures revealed that ΔN293 LTBP-1S was matrix associated via a transglutaminasedependent reaction, whereas ΔN441 LTBP-1S was not. This suggests that residues 294–441 are critical to the transglutaminase reactivity of LTBP-1S.
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Kumra, Heena, Valentin Nelea, Hana Hakami, Amelie Pagliuzza, Jelena Djokic, Jiongci Xu, Hiromi Yanagisawa, and Dieter P. Reinhardt. "Fibulin-4 exerts a dual role in LTBP-4L–mediated matrix assembly and function." Proceedings of the National Academy of Sciences 116, no. 41 (September 23, 2019): 20428–37. http://dx.doi.org/10.1073/pnas.1901048116.
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Elastogenesis is a hierarchical process by which cells form functional elastic fibers, providing elasticity and the ability to regulate growth factor bioavailability in tissues, including blood vessels, lung, and skin. This process requires accessory proteins, including fibulin-4 and -5, and latent TGF binding protein (LTBP)-4. Our data demonstrate mechanisms in elastogenesis, focusing on the interaction and functional interdependence between fibulin-4 and LTBP-4L and its impact on matrix deposition and function. We show that LTBP-4L is not secreted in the expected extended structure based on its domain composition, but instead adopts a compact conformation. Interaction with fibulin-4 surprisingly induced a conformational switch from the compact to an elongated LTBP-4L structure. This conversion was only induced by fibulin-4 multimers associated with increased avidity for LTBP-4L; fibulin-4 monomers were inactive. The fibulin-4–induced conformational change caused functional consequences in LTBP-4L in terms of binding to other elastogenic proteins, including fibronectin and fibrillin-1, and of LTBP-4L assembly. A transient exposure of LTBP-4L with fibulin-4 was sufficient to stably induce conformational and functional changes; a stable complex was not required. These data define fibulin-4 as a molecular extracellular chaperone for LTBP-4L. The altered LTBP-4L conformation also promoted elastogenesis, but only in the presence of fibulin-4, which is required to escort tropoelastin onto the extended LTBP-4L molecule. Altogether, this study provides a dual mechanism for fibulin-4 in 1) inducing a stable conformational and functional change in LTBP-4L, and 2) promoting deposition of tropoelastin onto the elongated LTBP-4L.
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Hyytiäinen, Marko, and Jorma Keski-Oja. "Latent TGF-β binding protein LTBP-2 decreases fibroblast adhesion to fibronectin." Journal of Cell Biology 163, no. 6 (December 22, 2003): 1363–74. http://dx.doi.org/10.1083/jcb.200309105.
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We have analyzed the effects of latent TGF-β binding protein 2 (LTBP-2) and its fragments on lung fibroblast adhesion. Quantitative cell adhesion assays indicated that fibroblasts do not adhere to full-length LTBP-2. Interestingly, LTBP-2 had dominant disrupting effects on the morphology of fibroblasts adhering to fibronectin (FN). Fibroblasts plated on LTBP-2 and FN substratum exhibited less adherent morphology and displayed clearly decreased actin stress fibers than cells plated on FN. These cells formed, instead, extensive membrane ruffles. LTBP-2 had no effects on cells adhering to collagen type I. Fibroblasts adhered weakly to the NH2-terminal fragment of LTBP-2. Unlike FN, this fragment did not augment actin stress fiber formation. Interestingly, the adhesion-mediating and cytoskeleton-disrupting effects were localized to the same NH2-terminal proline-rich region of LTBP-2. LTBP-2 and its antiadhesive fragment bound to FN in vitro, and the antiadhesive fragment associated with the extracellular matrix FN fibrils. These observations reveal a potentially important role for LTBP-2 as an antiadhesive matrix component.
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Taipale, J., K. Miyazono, CH Heldin, and J. Keski-Oja. "Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein." Journal of Cell Biology 124, no. 1 (January 1, 1994): 171–81. http://dx.doi.org/10.1083/jcb.124.1.171.
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The role of latent transforming growth factor-beta (TGF-beta) binding protein (LTBP) in the association of TGF-beta 1 to the extracellular matrix of cultured fibroblasts and HT-1080 fibrosarcoma cells was studied by immunochemical methods. The matrices were isolated from the cells, and the levels of LTBP and TGF-beta 1 were estimated by immunoblotting and immunoprecipitation. LTBP, TGF-beta 1, and its propeptide (latency-associated peptide, LAP) were found to associate to the extracellular matrix. Immunoblotting analysis indicated that treatment of the cells with plasmin resulted in a concomitant time and dose dependent release of both LTBP and TGF-beta 1 from the extracellular matrix to the supernatant. Comparison of molecular weights suggested that plasmin treatment resulted in the cleavage of LTBP from the high molecular weight fibroblast form to a form resembling the low molecular weight LTBP found in platelets. Pulse-chase and immunoprecipitation analysis indicated that both the free form of LTBP and LTBP complexed to latent TGF-beta were efficiently incorporated in the extracellular matrix, from where both complexes were slowly released to the culture medium. Addition of plasmin to the chase solution resulted, however, in a rapid release of LTBP from the matrix. Fibroblast derived LTBP was found to associate to the matrix of HT-1080 cells in a plasmin sensitive manner as shown by immunoprecipitation analysis. These results suggest that the latent form of TGF-beta 1 associates with the extracellular matrix via LTBP, and that the release of latent TGF-beta 1 from the matrix is a consequence of proteolytic cleavage(s) of LTBP.
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Dang, Zhi-Min, and Ce-Wen Nan. "Dielectric properties of LTNO ceramics and LTNO/PVDF composites." Ceramics International 31, no. 2 (January 2005): 349–51. http://dx.doi.org/10.1016/j.ceramint.2004.05.008.
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Yaseen, Muhammad, Wenxing Long, Farhan Khalid, Saraj Bahadur, and Hamza Armghan Noushahi. "Shifts in Community Vegetative Organs and Their Dissimilar Trade-Off Patterns in a Tropical Coastal Secondary Forest, Hainan Island, Southern China." Diversity 14, no. 10 (September 30, 2022): 823. http://dx.doi.org/10.3390/d14100823.
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The ecology of functional features highlights the importance of the leaf economic spectrum (LES) in understanding plant trade-offs between conservative and commercial resource use. However, it is still unclear whether changes in the plant attributes of various vegetative organs can be altered and whether the plant economic spectrum (PES) is categorized by multiple vegetative organs. We investigated a total of 12 functional features of 174 woody tree species, with leaf and stem attributes, on Hainan Island. We used principal component analysis (PCA) to analyze the changes in attributes and connections to understand how the plant trade-offs differ. We detected that stem organic matter (SOM) and stem organic carbon (SOC) contributed most to the first principal component, followed by leaf organic matter (LOM) and leaf organic carbon (LOC). Using Spearman correlation analysis, we determined that leaf total nitrogen (LTN) and specific leaf area (SLA), LTN and leaf total phosphorus (LTP), and finally stem total nitrogen (STN) and stem total phosphorus (STP) were positively significantly correlated. These significant variations in the traits of nutrients are regulated, while the morphological traits of aboveground vegetative organs are diverse. The coexistence of species and community assembly can increase our knowledge on the tropical coastal secondary forests. Furthermore, our outcomes can help us to better understand the restoration of habitats and green infrastructure design, suggesting that selecting different species across multiple trait axes can help ensure functionality at the maximum level.
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Dallas, S. L., K. Miyazono, T. M. Skerry, G. R. Mundy, and L. F. Bonewald. "Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein." Journal of Cell Biology 131, no. 2 (October 15, 1995): 539–49. http://dx.doi.org/10.1083/jcb.131.2.539.
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The role of the latent TGF-beta binding protein (LTBP) is unclear. In cultures of fetal rat calvarial cells, which form mineralized bonelike nodules, both LTBP and the TGF-beta 1 precursor localized to large fibrillar structures in the extracellular matrix. The appearance of these fibrillar structures preceded the appearance of type I collagen fibers. Plasmin treatment abolished the fibrillar staining pattern for LTBP and released a complex containing both LTBP and TGF-beta. Antibodies and antisense oligonucleotides against LTBP inhibited the formation of mineralized bonelike nodules in long-term fetal rat calvarial cultures. Immunohistochemistry of fetal and adult rat bone confirmed a fibrillar staining pattern for LTBP in vivo. These findings, together with the known homology of LTBP to the fibrillin family of proteins, suggest a novel function for LTBP, in addition to its role in matrix storage of latent TGF-beta, as a structural matrix protein that may play a role in bone formation.
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Annes, Justin P., Yan Chen, John S. Munger, and Daniel B. Rifkin. "Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1." Journal of Cell Biology 165, no. 5 (June 7, 2004): 723–34. http://dx.doi.org/10.1083/jcb.200312172.
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Transforming growth factor-βs (TGF-β) are secreted as inactive complexes containing the TGF-β, the TGF-β propeptide, also called the latency-associated protein (LAP), and the latent TGF-β binding protein (LTBP). Extracellular activation of this complex is a critical but incompletely understood step in TGF-β regulation. We have investigated the role of LTBP in modulating TGF-β generation by the integrin αVβ6. We show that even though αvβ6 recognizes an RGD on LAP, LTBP-1 is required for αVβ6-mediated latent TGF-β activation. The domains of LTBP-1 necessary for activation include the TGF-β propeptide-binding domain and a basic amino acid sequence (hinge domain) with ECM targeting properties. Our results demonstrate an LTBP-1 isoform-specific function in αVβ6-mediated latent TGF-β activation; LTBP-3 is unable to substitute for LTBP-1 in this assay. The results reveal a functional role for LTBP-1 in latent TGF-β activation and suggest that activation of specific latent complexes is regulated by distinct mechanisms that may be determined by the LTBP isoform and its potential interaction with the matrix.