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Stefani, Chiara, Antonella Sangalli, Elena Locatelli, Tania Federico, Giovanni Malerba, Maria Grazia Romanelli, Gustavo Adolfo Argañaraz et al. "Increased Prevalence of Unstable HLA-C Variants in HIV-1 Rapid-Progressor Patients". International Journal of Molecular Sciences 23, n.º 23 (27 de noviembre de 2022): 14852. http://dx.doi.org/10.3390/ijms232314852.
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HIV-1 infection in the absence of treatment results in progression toward AIDS. Host genetic factors play a role in HIV-1 pathogenesis, but complete knowledge is not yet available. Since less-expressed HLA-C variants are associated with poor HIV-1 control and unstable HLA-C variants are associated with higher HIV-1 infectivity, we investigated whether there was a correlation between the different stages of HIV-1 progression and the presence of specific HLA-C allotypes. HLA-C genotyping was performed using allele-specific PCR by analyzing a treatment-naïve cohort of 96 HIV-1-infected patients from multicentric cohorts in the USA, Canada, and Brazil. HIV-1-positive subjects were classified according to their different disease progression status as progressors (Ps, n = 48), long-term non-progressors (LTNPs, n = 37), and elite controllers (ECs, n = 11). HLA-C variants were classified as stable or unstable according to their binding stability to β2-microglobulin/peptide complex. Our results showed a significant correlation between rapid progression to AIDS and the presence of two or one unstable HLA-C variants (p-value: 0.0078, p-value: 0.0143, respectively). These findings strongly suggest a link between unstable HLA-C variants both at genotype and at allele levels and rapid progression to AIDS. This work provides further insights into the impact of host genetic factors on AIDS progression.
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Murakoshi, Hayato, Tomohiro Akahoshi, Madoka Koyanagi, Takayuki Chikata, Takuya Naruto, Rie Maruyama, Yoshiko Tamura et al. "Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes". Journal of Virology 89, n.º 10 (4 de marzo de 2015): 5330–39. http://dx.doi.org/10.1128/jvi.00020-15.
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ABSTRACTIdentification and characterization of CD8+T cells effectively controlling HIV-1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8+T cells have been only partially identified. In this study, we sought to identify CD8+T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identified 13 epitope-specific CD8+T cells controlling HIV-1 in Japanese individuals, though 9 of these epitopes were not previously reported. The breadths of the T cell responses to the 13 epitopes were inversely associated with plasma viral load (P= 2.2 × 10−11) and positively associated with CD4 count (P= 1.2 × 10−11), indicating strong synergistic effects of these T cells on HIV-1 controlin vivo. Nine of these epitopes were conserved among HIV-1 subtype B-infected individuals, whereas three out of four nonconserved epitopes were cross-recognized by the specific T cells. These findings indicate that these 12 epitopes are strong candidates for antigens for an AIDS vaccine. The present study highlighted a strategy to identify CD8+T cells controlling HIV-1 and demonstrated effective control of HIV-1 by those specific for 12 conserved or cross-reactive epitopes.IMPORTANCEHLA-B*27-restricted and HLA-B*57-restricted cytotoxic T lymphocytes (CTLs) play a key role in controlling HIV-1 in Caucasians and Africans, whereas it is unclear which CTLs control HIV-1 in Asian countries, where HLA-B*57 and HLA-B*27 are very rare. A recent study showed that HLA-B*67:01 and HLA-B*52:01-C*12:02 haplotypes were protective alleles in Japanese individuals, but it is unknown whether CTLs restricted by these alleles control HIV-1. In this study, we identified 13 CTLs controlling HIV-1 in Japan by using comprehensive and exhaustive methods. They included 5 HLA-B*52:01-restricted and 3 HLA-B*67:01-restricted CTLs, suggesting that these CTLs play a predominant role in HIV-1 control. The 13 CTLs showed synergistic effects on HIV-1 control. Twelve out of these 13 epitopes were recognized as conserved or cross-recognized ones. These findings strongly suggest that these 12 epitopes are candidates for antigens for AIDS vaccines.
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Yindom, Louis-Marie, Aleksandra Leligdowicz, Maureen P. Martin, Xiaojiang Gao, Ying Qi, Syed M. A. Zaman, Maarten Schim van der Loeff et al. "Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa". Journal of Virology 84, n.º 16 (2 de junio de 2010): 8202–8. http://dx.doi.org/10.1128/jvi.00116-10.
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ABSTRACT Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.
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Lazaryan, Aleksandr, Elena Lobashevsky, Joseph Mulenga, Etienne Karita, Susan Allen, Jianming Tang y Richard A. Kaslow. "Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans". Journal of Virology 80, n.º 12 (15 de junio de 2006): 6056–60. http://dx.doi.org/10.1128/jvi.02119-05.
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ABSTRACT Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.
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Mori, Masahiko, Ellen Leitman, Bruce Walker, Thumbi Ndung’u, Mary Carrington y Philip Goulder. "Impact of HLA Allele-KIR Pairs on HIV Clinical Outcome in South Africa". Journal of Infectious Diseases 219, n.º 9 (28 de diciembre de 2018): 1456–63. http://dx.doi.org/10.1093/infdis/jiy692.
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Abstract Background HLA class I contributes to HIV immune control through antigen presentation to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In contrast to investigations of CTL, studies of NK cells in HIV control through HLA-killer immunoglobulin-like receptor (KIR) interactions remain sparse in African cohorts. Methods Treatment-naive, chronically HIV-infected adults (N = 312) were recruited from South Africa, and the effects of HLA-KIR pairs on clinical outcome were analyzed. Results There was no significant difference in viral load among all subjects with HLA alleles from the HLA-C1 group (P = .1). However, differences in HLA-C type significantly influenced viremia among 247 KIR2DL3 positives (P = .04), suggesting that specific HLA-KIR interactions contribute to immune control. Higher viral load (P = .02) and lower CD4+ T-cell counts (P = .008) were observed in subjects with HLA-C*16:01+KIR2DL3+. Longitudinal analysis showed more rapid progression to AIDS among HLA-C*16:01+KIR2DL3+ subjects (adjusted hazard ratio 1.9, P = .03) than those without this genotype, independent of CD4+ T-cell count and viral load. Conclusions These results highlight the existence of unique anti-HIV innate immunity within distinct populations and the contribution of KIR on NK cells and some CTLs to the well-described HLA-mediated impact on HIV disease progression.
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Celsi, Fulvio, Eulalia Catamo, Giulio Kleiner, Paola Maura Tricarico, Josef Vuch y Sergio Crovella. "HLA-G/C, miRNAs, and Their Role in HIV Infection and Replication". BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/693643.
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In recent years, a number of different mechanisms regulating gene expressions, either in normal or in pathological conditions, have been discovered. This review aims to highlight some of the regulatory pathways involved during the HIV-1 infection and disease progression, focusing on the novel discovered microRNAs (miRNAs) and their relation with immune system’s agents. Human leukocyte antigen (HLA) family of proteins plays a key role because it is a crucial modulator of the immune response; here we will examine recent findings, centering especially on HLA-C and -G, novel players lately discovered to engage in modulation of immune system. We hope to provide novel perspectives useful to find out original therapeutic roads against HIV-1 infection and AIDS progression.
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Abitew, Abaineh Munshea, Ranbir Chander Sobti, Vijay Lakshmi Sharma y Ajay Wanchu. "Analysis of transporter associated with antigen presentation (TAP) genes polymorphisms with HIV-1 infection". Molecular and Cellular Biochemistry 464, n.º 1-2 (16 de noviembre de 2019): 65–71. http://dx.doi.org/10.1007/s11010-019-03649-x.
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AbstractHuman leukocyte antigen (HLA) class I molecules of the human major histocompatibility complex (MHC) play an important role in modulating immune response. HLA class I molecules present antigenic peptides to CD8+ T cells and thereby play a role in the immune surveillance of cells infected with viruses. TAP1 and TAP2 are MHC-II-encoded genes necessary for the generation of a cellular immune response and polymorphism of these genes can influence the specificity of peptides preferentially presented by the MHC class I molecules and the outcome of the immune response. Several studies implicated genetic variation in TAP genes to various immune-mediated and infectious diseases. To determine the correlation between HIV-1 infection and the TAP1 and TAP2 genes polymorphisms, we performed PCR–RFLP assay of these genes in 500 HIV-1 seropositives and the matched seronegative individuals. Statistical analysis of the data disclosed no correlation between TAP1 (C/T intron 7) gene polymorphism and HIV-1/AIDS disease. However, the current results demonstrated that the heterozygous A/G [OR (95% CI) 1.39 (1.06–1.83), P = 0.0171] and homozygous G/G [OR (95% CI) 3.38(1.56–7.46), P = 0.0010] variants of TAP2 (A/G exon 11) (T665A) gene are positively associated with an increased risk of HIV-1/AIDS infection. This case–control analysis might suggest a possible role of TAP2 (A/G exon 11) (T665A) gene in the susceptibility to HIV-1 infection and disease outcome among North Indian patients.
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Novitsky, V., P. Gilbert, T. Peter, M. F. McLane, S. Gaolekwe, N. Rybak, I. Thior et al. "Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection". Journal of Virology 77, n.º 2 (15 de enero de 2003): 882–90. http://dx.doi.org/10.1128/jvi.77.2.882-890.2003.
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ABSTRACT Virus-specific T-cell immune responses are important in restraint of human immunodeficiency virus type 1 (HIV-1) replication and control of disease. Plasma viral load is a key determinant of disease progression and infectiousness in HIV infection. Although HIV-1 subtype C (HIV-1C) is the predominant virus in the AIDS epidemic worldwide, the relationship between HIV-1C-specific T-cell immune responses and plasma viral load has not been elucidated. In the present study we address (i) the association between the level of plasma viral load and virus-specific immune responses to different HIV-1C proteins and their subregions and (ii) the specifics of correlation between plasma viral load and T-cell responses within the major histocompatibility complex (MHC) class I HLA supertypes. Virus-specific immune responses in the natural course of HIV-1C infection were analyzed in the gamma interferon (IFN-γ)-enzyme-linked immunospot assay by using synthetic overlapping peptides corresponding to the HIV-1C consensus sequence. For Gag p24, a correlation was seen between better T-cell responses and lower plasma viral load. For Nef, an opposite trend was observed where a higher T-cell response was more likely to be associated with a higher viral load. At the level of the HLA supertypes, a lower viral load was associated with higher T-cell responses to Gag p24 within the HLA A2, A24, B27, and B58 supertypes, in contrast to the absence of such a correlation within the HLA B44 supertype. The present study demonstrated differential correlations (or trends to correlation) in various HIV-1C proteins, suggesting (i) an important role of the HIV-1C Gag p24-specific immune responses in control of viremia and (ii) more rapid viral escape from immune responses to Nef with no restraint of plasma viral load. Correlations between the level of IFN-γ-secreting T cells and viral load within the MHC class I HLA supertypes should be considered in HIV vaccine design and efficacy trials.
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Rechavi, G., I. Ben-Bassat, M. Berkowicz, U. Martinowitz, F. Brok-Simoni, Y. Neumann, A. Vansover, T. Gotlieb-Stematsky y B. Ramot. "Molecular analysis of Burkitt's leukemia in two hemophilic brothers with AIDS". Blood 70, n.º 6 (1 de diciembre de 1987): 1713–17. http://dx.doi.org/10.1182/blood.v70.6.1713.1713.
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Abstract In two hemophilic brothers infected by the human immunodeficiency virus (HIV), Burkitt's leukemia developed within 1 year. Both patients were treated by aggressive chemotherapy, and both are still in complete remission for 23 and 14 months, respectively. Sera from both brothers contained anti-HIV antibodies. However, DNA extracted from the tumor cells, when analyzed by Southern blot using a cloned HIV probe, did not reveal HIV-related sequences. Hybridization experiments with an Epstein- Barr virus (EBV) probe revealed the presence of EBV-specific sequences in the tumors' DNA. In both patients' tumors rearranged c-myc genes were found. The rearrangements occurred in both genes 3′ to the third exon of c-myc, thereby suggesting that a variant chromosomal translocation took place in both cases. Indeed, karyotype analysis of the malignant cells of one of the patients revealed the variant t(2:8) translocation. In contrast to the majority of Burkitt's tumors carrying this translocation, which are kappa light-chain producers, cells of our patient expressed lambda chains. Furthermore, in both cases the lymphoblasts carried IgG on the surface, again an unusual finding in Burkitt's tumors. Finally, because both patients had an identical HLA phenotype, the role of genetic factors in the development of such tumors should be considered.
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Rechavi, G., I. Ben-Bassat, M. Berkowicz, U. Martinowitz, F. Brok-Simoni, Y. Neumann, A. Vansover, T. Gotlieb-Stematsky y B. Ramot. "Molecular analysis of Burkitt's leukemia in two hemophilic brothers with AIDS". Blood 70, n.º 6 (1 de diciembre de 1987): 1713–17. http://dx.doi.org/10.1182/blood.v70.6.1713.bloodjournal7061713.
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In two hemophilic brothers infected by the human immunodeficiency virus (HIV), Burkitt's leukemia developed within 1 year. Both patients were treated by aggressive chemotherapy, and both are still in complete remission for 23 and 14 months, respectively. Sera from both brothers contained anti-HIV antibodies. However, DNA extracted from the tumor cells, when analyzed by Southern blot using a cloned HIV probe, did not reveal HIV-related sequences. Hybridization experiments with an Epstein- Barr virus (EBV) probe revealed the presence of EBV-specific sequences in the tumors' DNA. In both patients' tumors rearranged c-myc genes were found. The rearrangements occurred in both genes 3′ to the third exon of c-myc, thereby suggesting that a variant chromosomal translocation took place in both cases. Indeed, karyotype analysis of the malignant cells of one of the patients revealed the variant t(2:8) translocation. In contrast to the majority of Burkitt's tumors carrying this translocation, which are kappa light-chain producers, cells of our patient expressed lambda chains. Furthermore, in both cases the lymphoblasts carried IgG on the surface, again an unusual finding in Burkitt's tumors. Finally, because both patients had an identical HLA phenotype, the role of genetic factors in the development of such tumors should be considered.
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Liang, Binhua, Ma Luo, T. Blake Ball, Steven J. M. Jones y Francis A. Plummer. "QUASI analysis of host immune responses to Gag polyproteins of human immunodeficiency virus type 1 by a systematic bioinformatics approachThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 88, n.º 4 (agosto de 2010): 671–81. http://dx.doi.org/10.1139/o10-002.
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There is a consensus that Gag-specific cytotoxic T lymphocyte (CTL) response plays a key role in the immune control of human immunodeficiency virus type 1 (HIV-1) infection. In this study, we analyzed all currently available gag sequences in the Los Alamos HIV sequence database and identified positive selection (PS) sites likely restricted by the host immune responses. We found that between 23.4% and 47.4% of PS sites were shared by clades A, B, and C of Gag, indicating similar positive selection pressure on Gag in different subtypes of HIV-1. Furthermore, a significant correlation was observed between the combined CTL and antibody responses and PS sites. The Gag regions of free from PS contained 9 CTL epitopes restricted by 11 HLA class I alleles associated with disease progression to acquired immune deficiency syndrome (AIDS). These analyses provide information important for the identification of cross-clade epitopes and development of a global HIV-1 vaccine.
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Siswantining, Titin, Alhadi Bustamam, Devvi Sarwinda, Saskya Mary Soemartojo, Moh Abdul Latief, Elke Annisa Octaria, Anggrainy Togi Marito Siregar, Oon Septa, Herley Shaori Al-Ash y Noval Saputra. "Triclustering method for finding biomarkers in human immunodeficiency virus-1 gene expression data". Mathematical Biosciences and Engineering 19, n.º 7 (2022): 6743–63. http://dx.doi.org/10.3934/mbe.2022318.
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<abstract><p>HIV-1 is a virus that destroys CD4 + cells in the body's immune system, causing a drastic decline in immune system performance. Analysis of HIV-1 gene expression data is urgently needed. Microarray technology is used to analyze gene expression data by measuring the expression of thousands of genes in various conditions. The gene expression series data, which are formed in three dimensions, are analyzed using triclustering. Triclustering is an analysis technique for 3D data that aims to group data simultaneously into rows and columns across different times/conditions. The result of this technique is called a tricluster. A tricluster is a subspace in the form of a subset of rows, columns, and time/conditions. In this study, we used the $ \delta $-Trimax, THD Tricluster, and MOEA methods by applying different measures, namely, transposed virtual error, the New Residue Score, and the Multi Slope Measure. The gene expression data consisted of 22,283 probe gene IDs, 40 observations, and four conditions: normal, acute, chronic, and non-progressor. Tricluster evaluation was carried out based on intertemporal homogeneity. An analysis of the probe ID gene that affects AIDS was carried out through this triclustering process. Based on this analysis, a gene symbol which is biomarkers associated with AIDS due to HIV-1, HLA-C, was found in every condition for normal, acute, chronic, and non-progressive HIV-1 patients.</p></abstract>
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Novitsky, V., N. Rybak, M. F. McLane, P. Gilbert, P. Chigwedere, I. Klein, S. Gaolekwe et al. "Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design". Journal of Virology 75, n.º 19 (1 de octubre de 2001): 9210–28. http://dx.doi.org/10.1128/jvi.75.19.9210-9228.2001.
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ABSTRACT The most severe human immunodeficiency virus type 1 (HIV-1) epidemic is occurring in southern Africa. It is caused by HIV-1 subtype C (HIV-1C). In this study we present the identification and analysis of cumulative cytotoxic T-lymphocyte (CTL) responses in the southern African country of Botswana. CTLs were shown to be an important component of the immune response to control HIV-1 infection. The definition of optimal and dominant epitopes across the HIV-1C genome that are targeted by CTL is critical for vaccine design. The characteristics of the predominant virus that causes the HIV-1 epidemic in a certain geographic area and also the genetic background of the population, through the distribution of common HLA class I alleles, might impact dominant CTL responses in the vaccinee and in the general population. The enzyme-linked immunospot (Elispot) gamma interferon assay has recently been shown to be a reliable tool to map optimal CTL epitopes, correlating well with other methods, such as intracellular staining, tetramer staining, and the classical chromium release assay. Using Elispot with overlapping synthetic peptides across Gag, Tat, Rev, and Nef, we analyzed HIV-1C-specific CTL responses of HIV-1-infected blood donors. Profiles of cumulative Elispot-based CTL responses combined with diversity and sequence consensus data provide an additional characterization of immunodominant regions across the HIV-1C genome. Results of the study suggest that the construction of a poly-epitope subtype-specific HIV-1 vaccine that includes multiple copies of immunodominant CTL epitopes across the viral genome, derived from predominant HIV-1 viruses, might be a logical approach to the design of a vaccine against AIDS.
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Egan, Michael A., Marcelo J. Kuroda, Gerald Voss, Jörn E. Schmitz, William A. Charini, Carol I. Lord, Meryl A. Forman y Norman L. Letvin. "Use of Major Histocompatibility Complex Class I/Peptide/β2M Tetramers To Quantitate CD8+ Cytotoxic T Lymphocytes Specific for Dominant and Nondominant Viral Epitopes in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys". Journal of Virology 73, n.º 7 (1 de julio de 1999): 5466–72. http://dx.doi.org/10.1128/jvi.73.7.5466-5472.1999.
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ABSTRACT To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8+ CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8+ CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/β2m complexes. All SHIV-infected Mamu-A*01+ rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8+ CTL response is dominant and the p41A- and p68A-specific CD8+ CTL responses are nondominant. These results indicate that CD8+CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8+ CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach.
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White, Yohann, Geoffrey Barrow, David Gilbert, Tanya Clarke, Adedamola Soyibo, Andre McGregor, Dewayne Stennett et al. "Profound Immune Exhaustion and Downregulation Of Interleukin-7 Alpha Receptor (CD127) In CD8 and CD4 T-Cell Subsets In Jamaican Patients Co-Infected With Human T-Cell Lymphotropic Virus Type-1 and Human Immunodeficiency Virus Type-1 Despite Normal Or Above Normal CD4 Counts". Blood 122, n.º 21 (15 de noviembre de 2013): 3498. http://dx.doi.org/10.1182/blood.v122.21.3498.3498.
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Abstract Background Next to Sub-Saharan Africa, the Caribbean has the second highest prevalence of human immunodeficiency virus type 1 (HIV-1) infection; and human T-cell lymphotropic virus type 1 (HTLV-1), another human retrovirus, is also endemic. Fewer than five percent of persons with HTLV-1, predominantly transmitted through breast feeding, progress to any of the myriad associated diseases, including adult T-cell leukemia, HTLV-1 associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP), or polymyositis. HTLV-1, through its oncoprotein-like transactivating (Tax) protein, results in aberrant proliferation of CD4 cells through interaction with cell cycle regulators, and activation of nuclear factor kappa B and the interleukin-2 pathway. Elevated CD4 counts, often above normal range, observed in patients with HTLV-1/HIV-1 co-infection, may be spurious, posing a challenge for laboratory monitoring of lymphoproliferative disorders or HIV-1 progression. Methods We compared CD4 counts, HIV-1 viral load, and clinical parameters in a cohort of patients co-infected with HTLV-1 and HIV-1 (syphilis, hepatitis B and C non-reactive), with controls with HIV-1 infection only matched for age, sex, and duration of antiretroviral therapy, as well as donors without HTLV-1 or HIV-1 infection. We used flow cytometry to characterize CD4 and CD8 naïve and memory T-cell subsets, expression of T-cell survival and homeostatic cytokine interleukin-7 alpha receptor (CD127), and examined the role of co-inhibitory programmed death-1 in HTLV-1 infected (intracellular HTLV-1 Tax protein-expressing) and HIV-1 infected (intracellular HIV-1 Gag protein-expressing) CD4 cells in immune evasion. Additionally, we assessed the effects of exogenous interleukin-7 (IL-7) and programmed death-1 pathway blockade on the function of responding CD8 cytotoxic T-lymphocyte (CTL) subsets ex vivo. Results All patients with HTLV-1 and HIV-1 co-infection (n = 5) were female and of median age 42 years (range, 22 to 49 years), with normal or above normal CD4 counts. Four of five patients with HTLV-1/HIV-1 co-infection were WHO Stage 4 HIV/AIDS at diagnosis (e.g., oesophageal candidiasis, HIV nephropathy). Median duration since diagnosis with HIV-1 infection was six years (range, 1 to 18 years), and unexpectedly high CD4 count was the reason for HTLV-1/2 testing in all cases. Nadir CD4 count among patients with HTLV-1/HIV-1 co-infection was significantly higher than controls with HIV-1 infection only (n = 12) matched for age, sex, and duration of antiretroviral therapy (median 684, range 467 to 1474; and median 36, range, 8 to 352 cells per microliter, respectively; p = 0.007, Mann-Whitney U test). Flow cytometric analyses of CD8 and CD4 T-cell memory subsets revealed more profound loss of CD127 in the CD8 compared to the CD4 compartment; and CD8(+) effector memory T-cells showed the most significant downregulation of CD127 when patients with HTLV-1/HIV-1 co-infection were compared with seronegative donors (40.3±17.0%, n =5; and 73.1±7.48%, n = 10, respectively; p = 0.032, Mann-Whitney U). In ex vivo experiments in the context of peripheral blood mononuclear cells, preliminary data suggest that patients with HTLV-1/HIV-1 co-infection have impaired CD8(+) CTL function in response to HLA-restricted HTLV-1 Tax11-19 and cytomegalovirus (CMV) pp65 peptide stimulation. Further, we sought to describe expression of co-inhibitory marker programmed death-1 ligand (PDL1) on intracellular HTLV-1 Tax protein- as well as intracellular HIV-1 Gag protein-expressing CD4 cells. Blockade of PDL1 resulted in partial recovery of CTL function in patients with HTLV-1/HIV co-infection, and enhanced killing of target cells infected with either HTLV-1 or HIV-1. Conclusions Patients with HTLV-1/HIV-1 co-infection show profound CTL exhaustion; and CD4 cells, although within or above normal CD4 count range, show aberrant naïve and memory T-cell distribution and possible immune evasion by upregulation of the programmed death-1 pathway, blockade of which showed a tendency towards enhanced virus-specific CTL function and killing of target cells infected with HTLV-1 or HIV-1. Disclosures: No relevant conflicts of interest to declare.
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Prado, Julia G., Andrew Prendergast, Christina Thobakgale, Claudia Molina, Gareth Tudor-Williams, Thumbi Ndung'u, Bruce D. Walker y Philip Goulder. "Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate". Journal of Virology 84, n.º 1 (14 de octubre de 2009): 492–502. http://dx.doi.org/10.1128/jvi.01743-09.
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ABSTRACT Human immunodeficiency virus (HIV)-infected infants in the developing world typically progress to AIDS or death within the first 2 years of life. However, a minority progress relatively slowly. This study addresses the potential contribution of viral factors to HIV disease progression in eight infants selected from a well-characterized cohort of C clade HIV-infected infants, monitored prospectively from birth in Durban, South Africa. Three infants were defined as “progressors,” and five were defined as “slow progressors.” We observed that slow-progressor infants carry HIV isolates with significantly lower replicative capacity compared to virus from progressors. Furthermore, our data suggest a link between the attenuated viral phenotype and HLA-B* 57/5801 epitope-specific Gag mutational patterns of the transmitted virus and not to coreceptor usage or to the presence of Nef deletions or insertions. These data underline the importance of virus-host interactions and highlight the contribution of viral attenuation through Gag-specific CD8+ T-cell escape mutations, among other factors, in the control of pediatric HIV infection.
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Hopfensperger, Kristina, Jonathan Richard, Christina M. Stürzel, Frederic Bibollet-Ruche, Richard Apps, Marie Leoz, Jean-Christophe Plantier et al. "Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2". mBio 11, n.º 4 (14 de julio de 2020). http://dx.doi.org/10.1128/mbio.00782-20.
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ABSTRACT HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo, we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells. IMPORTANCE Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4+ T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response.
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Parolini, Francesca, Priscilla Biswas, Michela Serena, Francesca Sironi, Valentina Muraro, Elisabetta Guizzardi, Lucia Cazzoletti et al. "Stability and Expression Levels of HLA-C on the Cell Membrane Modulate HIV-1 Infectivity". Journal of Virology 92, n.º 1 (25 de octubre de 2017). http://dx.doi.org/10.1128/jvi.01711-17.
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ABSTRACTHLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes and the triggering of activating killer immunoglobulin-like receptors on NK cells, whereas lower levels may provide poor HIV-1 control and rapid progression to AIDS. We characterized the relative amounts of HLA-C heterotrimers (heavy chain/β2microglobulin [β2m]/peptide) and HLA-C free heavy chains on peripheral blood mononuclear cells (PBMCs) from healthy blood donors harboring both alleles with stable or unstable binding to β2m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMCs with various allotypes. We observed significant differences in HLA-C heterotrimer stability and in expression levels. We found that R5 HIV-1 virions produced by PBMCs harboring unstable HLA-C alleles were more infectious than those produced by PBMCs carrying the stable variants. We propose that HIV-1 infectivity might depend both on the amounts of HLA-C molecules and on their stability as trimeric complex. According to this model, individuals with low-expression HLA-C alleles and unstable binding to β2m/peptide might have worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication.IMPORTANCEFollowing HIV-1 infection, some people advance rapidly to AIDS while others have slow disease progression. HLA-C, a molecule involved in immunity, is a key determinant of HIV-1 control. Here we reveal how HLA-C variants contribute to the modulation of viral infectivity. HLA-C is present on the cell surface in two different conformations. The immunologically active conformation is part of a complex that includes β2microglobulin/peptide; the other conformation is not bound to β2microglobulin/peptide and can associate with HIV-1, increasing its infectivity. Individuals with HLA-C variants with a predominance of immunologically active conformations would display stronger immunity to HIV-1, reduced viral infectivity and effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from β2microglobulin/peptide would have a reduced immunological response to HIV-1 and produce more infectious virions. This study provides new information that could be useful in the design of novel vaccine strategies and therapeutic approaches to HIV-1.
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de Groot, Natasja G., Corrine M. C. Heijmans, Arnoud H. de Ru, Nel Otting, Frits Koning, Peter A. van Veelen y Ronald E. Bontrop. "The HLA A03 Supertype and Several Pan Species Major Histocompatibility Complex Class I A Allotypes Share a Preference for Binding Positively Charged Residues in the F Pocket: Implications for Controlling Retroviral Infections". Journal of Virology 94, n.º 9 (19 de febrero de 2020). http://dx.doi.org/10.1128/jvi.01960-19.
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ABSTRACT The major histocompatibility complex (MHC) class I region of humans, chimpanzees (Pan troglodytes), and bonobos (Pan paniscus) is highly similar, and orthologues of HLA-A, -B, and -C are present in both Pan species. Based on functional characteristics, the different HLA-A allotypes are classified into different supertypes. One of them, the HLA A03 supertype, is widely distributed among different human populations. All contemporary known chimpanzee and bonobo MHC class I A allotypes cluster genetically into one of the six HLA-A families, the HLA-A1/A3/A11/A30 family. We report here that the peptide-binding motif of the Patr-A*05:01 allotype, which is commonly present in a cohort of western African chimpanzees, has a strong preference for binding peptides with basic amino acids at the carboxyl terminus. This phenomenon is shared with the family members of the HLA A03 supertype. Based on the chemical similarities in the peptide-binding pocket, we inferred that the preference for binding peptides with basic amino acids at the carboxyl terminus is widely present among the human, chimpanzee, and bonobo MHC-A allotypes. Subsequent in silico peptide-binding predictions illustrated that these allotypes have the capacity to target conserved parts of the proteome of human immunodeficiency virus type 1 (HIV-1) and the simian immunodeficiency virus SIVcpz. IMPORTANCE Most experimentally infected chimpanzees seem to control an HIV-1 infection and are therefore considered to be relatively resistant to developing AIDS. Contemporary free-ranging chimpanzees may carry SIVcpz, and there is evidence for AIDS-like symptoms in these free-ranging animals, whereas SIV infections in bonobos appear to be absent. In humans, the natural control of an HIV-1 infection is strongly associated with the presence of particular HLA class I allotypes. The ancestor of the contemporary living chimpanzees and bonobos survived a selective sweep targeting the MHC class I repertoire. We have put forward a hypothesis that this may have been caused by an ancestral retroviral infection similar to SIVcpz. Characterization of the relevant MHC allotypes may contribute to understanding the shaping of their immune repertoire. The abundant presence of MHC-A allotypes that prefer peptides with basic amino acids at the C termini suggests that these molecules may contribute to the control of retroviral infections in humans, chimpanzees, and bonobos.
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DAMAR ÇAKIRCA, Tuba. "Şanlıurfa İlinde HIV/AIDS: 114 Olgunun Retrospektif Analizi, Tek Merkez Deneyimi". Harran Üniversitesi Tıp Fakültesi Dergisi, 27 de diciembre de 2022, 594–99. http://dx.doi.org/10.35440/hutfd.1185979.
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Özet Amaç: Kliniğimizde takip edilen HIV/AIDS olgularının genel özellikleri ile klinik ve laboratuvar verilerinin irdelenmesidir. Materyal ve Metod: Bu retrospektif kesitsel çalışmaya Ocak 2020-Haziran 2022 tarihleri arasında merkezimizde takip edilen 114 HIV/AIDS hastası dahil edildi. Bulgular: Olguların %81.6’sı erkek olup, ortanca yaşı 34 yıl idi. En çok tespit edilen bulaş yolu cinsel ilişkiydi (%57.9 heteroseksüel, %37.7 homoseksüel). Tanıya götüren en sık neden %31.6 oranla klinik bulguların olmasıydı. Tedavi öncesi ortanca HIV-RNA değeri 49786,5 IU/mL, CD4 ortanca değeri 322 hücre/mm3 saptandı. Hastalar CDC Sürveyans Ölçütlerine göre sınıflandırıldığında; 21 hasta Evre 1, 58 hasta Evre 2, 28 hasta ise Evre 3’de iken tanı almıştı. CDC Klinik kategorilerine bakıldığında ise; 85 hasta kategori A, 22 hasta kategori B ve 7 hasta kategori C, yani AIDS evresindeydi. Başvuru sırasında en sık eşlik eden koenfeksiyonlar genital kondilom (%22.8) ve sifilizdi (%17.5). HLA-B57 testi 2 hastada pozitif saptandı. Kemik dansitometrileri yapılan 104 hastanın 51’inde osteopeni (%44.7), 6’sında osteoporoz (%5.3) saptandı. Hastaların %57.9’da Toxoplazma gondii IgG antikoru pozitifti. En çok başlanılan antiretroviral tedavi rejimi Tenofovir disoproksil/Emtrisitabin/Dolutegravir olup, en çok devam eden Tenofovir Alafenamit/ Emtrisitabin/Biktegravirdi. Sonuç: Sonuç olarak HIV/AIDS insidansı dünyada azalmasına rağmen, ülkemizde artmaktadır. Bununla birlikte son yıllarda hastalarımızın cinsel kimliklerini daha rahat ifade edebildikleri ve bu nedenle bulaş yolu bilinmeyenlerin oranının azaldığı görülmüştür. Ek olarak, çalışmamızda AIDS evresinde başvuruların ve fırsatçı enfeksiyon görülme sıklığının azaldığı bununla birlikte cinsel yolla bulaşan diğer enfeksiyon oranlarının arttığı gözlenmiştir.
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Hatchwell, Eli, Edward B. Smith, Shapour Jalilzadeh, Christopher D. Bruno, Yassine Taoufik, Houria Hendel-Chavez, Roland Liblau et al. "Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies". Frontiers in Neurology 13 (14 de diciembre de 2022). http://dx.doi.org/10.3389/fneur.2022.1016377.
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BackgroundProgressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.g., leukemias, lymphomas, and multiple myeloma), autoimmune disorders (e.g., psoriasis, rheumatoid arthritis, and systemic lupus erythematosus), and organ transplants. In some patients, iatrogenic (i.e., drug-induced) PML occurs as a serious adverse event from exposure to immunosuppressant therapies used to treat their disease (e.g., hematological malignancies and multiple sclerosis). While JCV infection and immunosuppression are necessary, they are not sufficient to cause PML.MethodsWe hypothesized that patients may also have a genetic susceptibility from the presence of rare deleterious genetic variants in immune-relevant genes (e.g., those that cause inborn errors of immunity). In our prior genetic study of 184 PML cases, we discovered 19 candidate PML risk variants. In the current study of another 152 cases, we validated 4 of 19 variants in both population controls (gnomAD 3.1) and matched controls (JCV+ multiple sclerosis patients on a PML-linked drug ≥ 2 years).ResultsThe four variants, found in immune system genes with strong biological links, are: C8B, 1-57409459-C-A, rs139498867; LY9 (alias SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; STXBP2, 19-7712287-G-C, rs35490401. Carriers of any one of these variants are shown to be at high risk of PML when drug-exposed PML cases are compared to drug-exposed matched controls: P value = 3.50E-06, OR = 8.7 [3.7–20.6]. Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.ConclusionFor the first time, a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug in order to decrease the incidence of PML and enable safer use of highly effective therapies used to treat their underlying disease.