Journal articles: 'HIV-1, HLA-C'

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Zipeto, Donato, and Alberto Beretta. "C3 HIV-1 Env and HLA-C." JAIDS Journal of Acquired Immune Deficiency Syndromes 59 (April 2012): 77. http://dx.doi.org/10.1097/01.qai.0000413798.79651.e7.

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Apps, Richard, Gregory Q. Del Prete, Pramita Chatterjee, Abigail Lara, Zabrina L. Brumme, Mark A. Brockman, Stuart Neil, et al. "HIV-1 Vpu Mediates HLA-C Downregulation." Cell Host & Microbe 19, no. 5 (May 2016): 686–95. http://dx.doi.org/10.1016/j.chom.2016.04.005.

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Barker, Edward, and David T. Evans. "HLA-C Downmodulation by HIV-1 Vpu." Cell Host & Microbe 19, no. 5 (May 2016): 570–71. http://dx.doi.org/10.1016/j.chom.2016.04.023.

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Muccini, Camilla, Monica Guffanti, Vincenzo Spagnuolo, Massimo Cernuschi, Laura Galli, Alba Bigoloni, Andrea Galli, Andrea Poli, Sara Racca, and Antonella Castagna. "Association between low levels of HIV-1 DNA and HLA class I molecules in chronic HIV-1 infection." PLOS ONE 17, no. 3 (March 15, 2022): e0265348. http://dx.doi.org/10.1371/journal.pone.0265348.

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Background HLA-B27 and -B57 were found in people with low levels of HIV-1 DNA, suggesting that HLA class I molecules may influence the size of HIV-1 reservoir. Aim of the study was to explore the association between HLA class I molecules and HIV-1 DNA in people with chronic HIV-1 infection. Methods Post-hoc analysis of the APACHE trial, on adults with chronic HIV-1 infection, prolonged suppressive antiretroviral therapy and good immunological profile. HIV-1 DNA was quantified in peripheral blood mononuclear cells (PBMCs); HLA-A, -B and -C were tested on genomic DNA. Crude odds ratios (OR) with their respective 95% Wald confidence intervals (95% CIs) were estimated by univariable logistic regression for HLAs with a p-value <0.10. Results We found 78 and 18 patients with HIV-1 DNA ≥100 copies/106PBMCs and with HIV-1 DNA <100 copies/106PBMCs, respectively. HLA-A24 was present in 21 (29.6%) participants among subjects with HIV-1 DNA ≥100 copies/106PBMCs and 1 (5.9%) among those with HIV-1 DNA <100 copies/106PBMCs (OR = 5.67, 95%CI = 0.79–46.03; p = 0.105); HLA-B39 was present in 1 (1.4%) with HIV-1 DNA ≥100 copies/106PBMCs and in 3 (17.6%) with HIV-1 DNA <100 copies/106PBMCs (OR = 13.71, 95%CI = 1.33–141.77; p = 0.028) and HLA-B55 in 3 (4.2%) and 3 (17.6%), respectively (OR = 4.43, 95%CI = 0.81–24.29; p = 0.087). All the three patients with HLA-B39 and HIV-1 DNA <100 copies/106PBMCs did not have HLA-A24. Conclusions In patients with HIV-1 infection who maintained a good virological and immunological profile, HLA-B39 and -B55 may be associated with lower levels of HIV-1 DNA.

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Bachtel, Nathaniel D., Gisele Umviligihozo, Suzanne Pickering, Talia M. Mota, Hua Liang, Gregory Q. Del Prete, Pramita Chatterjee, et al. "HLA-C downregulation by HIV-1 adapts to host HLA genotype." PLOS Pathogens 14, no. 9 (September 4, 2018): e1007257. http://dx.doi.org/10.1371/journal.ppat.1007257.

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Specht, Anke, Amalio Telenti, Raquel Martinez, Jacques Fellay, Elizabeth Bailes, David T. Evans, Mary Carrington, Beatrice H. Hahn, David B. Goldstein, and Frank Kirchhoff. "Counteraction of HLA-C-Mediated Immune Control of HIV-1 by Nef." Journal of Virology 84, no. 14 (May 12, 2010): 7300–7311. http://dx.doi.org/10.1128/jvi.00619-10.

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ABSTRACT A host genetic variant (−35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective −35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the “protective” high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective −35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the −35TT genotype. Since the latter Nef functions all influence the stimulation of CD4+ T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common −35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation.

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Adnan, Sama, Arumugam Balamurugan, Alicja Trocha, Michael S. Bennett, Hwee L. Ng, Ayub Ali, Christian Brander, and Otto O. Yang. "Nef interference with HIV-1–specific CTL antiviral activity is epitope specific." Blood 108, no. 10 (November 15, 2006): 3414–19. http://dx.doi.org/10.1182/blood-2006-06-030668.

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AbstractHIV-1 Nef and HIV-1–specific cytotoxic T lymphocytes (CTLs) have important and opposing roles in the immunopathogenesis of HIV-1 infection. Nef-mediated down-modulation of HLA class I on infected cells can confer resistance to CTL clearance, but the factors determining the efficiency of this process are unknown. This study examines the impact of Nef on the antiviral activity of several CTL clones recognizing epitopes from early and late HIV-1 proteins, restricted by HLA-A, -B, and -C molecules. CTL-targeting epitopes in early proteins remained susceptible to the effects of Nef, although possibly to a lesser degree than CTL-targeting late protein epitopes, indicating that significant Nef-mediated HLA down-regulation can precede even the presentation of early protein-derived epitopes. However, HLA-C–restricted CTLs were unaffected by Nef, consistent with down-regulation of cell-surface HLA-A and -B but not HLA-C molecules. Thus, CTLs vary dramatically in their susceptibility to Nef interference, suggesting differences in the relative importance of HLA-A– and HLA-B– versus HLA-C–restricted CTLs in vivo. The data thus indicate that HLA-C–restricted CTLs may have an under-appreciated antiviral role in the setting of Nef in vivo and suggest a benefit of promoting HLA-C–restricted CTLs for immunotherapy or vaccine development.

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Nii-Trebi, Nicholas I., Saori Matsuoka, Ai Kawana-Tachikawa, Evelyn Y. Bonney, Christopher Z. Abana, Sampson B. Ofori, Taketoshi Mizutani, et al. "Super high-resolution single-molecule sequence-based typing of HLA class I alleles in HIV-1 infected individuals in Ghana." PLOS ONE 17, no. 6 (June 2, 2022): e0269390. http://dx.doi.org/10.1371/journal.pone.0269390.

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Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.

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Ende, Zachary, Martin J. Deymier, Daniel T. Claiborne, Jessica L. Prince, Daniela C. Mónaco, William Kilembe, Susan A. Allen, and Eric Hunter. "HLA Class I Downregulation by HIV-1 Variants from Subtype C Transmission Pairs." Journal of Virology 92, no. 7 (January 10, 2018): e01633-17. http://dx.doi.org/10.1128/jvi.01633-17.

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ABSTRACTHIV-1 downregulates human leukocyte antigen A (HLA-A) and HLA-B from the surface of infected cells primarily to evade CD8 T cell recognition. HLA-C was thought to remain on the cell surface and bind inhibitory killer immunoglobulin-like receptors, preventing natural killer (NK) cell-mediated suppression. However, a recent study found HIV-1 primary viruses have the capacity to downregulate HLA-C. The goal of this study was to assess the heterogeneity of HLA-A, HLA-B, and HLA-C downregulation among full-length primary viruses from six chronically infected and six newly infected individuals from transmission pairs and to determine whether transmitted/founder variants exhibit common HLA class I downregulation characteristics. We measured HLA-A, HLA-B, HLA-C, and total HLA class I downregulation by flow cytometry of primary CD4 T cells infected with 40 infectious molecular clones. Primary viruses mediated a range of HLA class I downregulation capacities (1.3- to 6.1-fold) which could differ significantly between transmission pairs. Downregulation of HLA-C surface expression on infected cells correlated with susceptibility toin vitroNK cell suppression of virus release. Despite this, transmitted/founder variants did not share a downregulation signature and instead were more similar to the quasispecies of matched donor partners. These data indicate that a range of viral abilities to downregulate HLA-A, HLA-B, and HLA-C exist within and between individuals that can have functional consequences on immune recognition.IMPORTANCESubtype C HIV-1 is the predominant subtype involved in heterosexual transmission in sub-Saharan Africa. Authentic subtype C viruses that contain natural sequence variations throughout the genome often are not used in experimental systems due to technical constraints and sample availability. In this study, authentic full-length subtype C viruses, including transmitted/founder viruses, were examined for the ability to disrupt surface expression of HLA class I molecules, which are central to both adaptive and innate immune responses to viral infections. We found that the HLA class I downregulation capacity of primary viruses varied, and HLA-C downregulation capacity impacted viral suppression by natural killer cells. Transmitted viruses were not distinct in the capacity for HLA class I downregulation or natural killer cell evasion. These results enrich our understanding of the phenotypic variation existing among natural HIV-1 viruses and how that might impact the ability of the immune system to recognize infected cells in acute and chronic infection.

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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, no. 23 (November 27, 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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Kulpa, Deanna A., and Kathleen L. Collins. "The emerging role of HLA-C in HIV-1 infection." Immunology 134, no. 2 (September 6, 2011): 116–22. http://dx.doi.org/10.1111/j.1365-2567.2011.03474.x.

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Derrien, Muriel, Nathalie Pizzato, Guillermina Dolcini, Elisabeth Menu, Gérard Chaouat, Françoise Lenfant, Françoise Barré-Sinoussi, and Philippe Le Bouteiller. "Human immunodeficiency virus 1 downregulates cell surface expression of the non-classical major histocompatibility class I molecule HLA-G1." Journal of General Virology 85, no. 7 (July 1, 2004): 1945–54. http://dx.doi.org/10.1099/vir.0.79867-0.

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Human immunodeficiency virus 1 (HIV-1) downregulates cell surface expression of HLA-A and HLA-B but not HLA-C or HLA-E to ultimately escape immune defences. Here, it is shown that cell surface expression of the non-classical HLA-G1 is also downregulated by HIV-1, by using co-transfection experiments and infection with cell-free HIV-1 of HLA-G1-expressing U87 glioma cells or macrophages in primary culture. Moreover, co-transfection experiments using proviruses deleted in either nef or vpu or plasmids encoding HIV-1 Nef and Vpu mixed together with a HLA-G1-expressing construct demonstrated that HLA-G1 downregulation is Nef-independent and Vpu-dependent, contrasting with the Nef- and Vpu-dependent HLA-A2 downregulation. Together, these results show that the decrease of HLA-A2 and HLA-G1 caused by HIV-1 occurs through distinct mechanisms.

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Akahoshi, Tomohiro, Hiroyuki Gatanaga, Nozomi Kuse, Takayuki Chikata, Madoka Koyanagi, Naoki Ishizuka, Chanson J. Brumme, et al. "T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics." PLOS Pathogens 16, no. 12 (December 28, 2020): e1009177. http://dx.doi.org/10.1371/journal.ppat.1009177.

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HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128–135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.

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Lazaryan, Aleksandr, Elena Lobashevsky, Joseph Mulenga, Etienne Karita, Susan Allen, Jianming Tang, and Richard A. Kaslow. "Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans." Journal of Virology 80, no. 12 (June 15, 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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Stoll, Andrej, Silke Bergmann, Christiane Mummert, Sandra M. Mueller-Schmucker, Bernd M. Spriewald, Ellen G. Harrer, and Thomas Harrer. "Identification of HLA-C restricted, HIV-1-specific CTL epitopes by peptide induced upregulation of HLA-C expression." Journal of Immunological Methods 418 (March 2015): 9–18. http://dx.doi.org/10.1016/j.jim.2015.01.005.

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Matucci, Andrea, Paola Rossolillo, Miriam Baroni, Antonio G. Siccardi, Alberto Beretta, and Donato Zipeto. "HLA-C increases HIV-1 infectivity and is associated with gp120." Retrovirology 5, no. 1 (2008): 68. http://dx.doi.org/10.1186/1742-4690-5-68.

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Matucci, Andrea, Paola Rossolillo, Marco Turci, Pierpaolo Racchiolli, Antonio G. Siccardi, Alberto Beretta, and Donato Zipeto. "137 Presence and role of HLA-C in HIV-1 infection." JAIDS Journal of Acquired Immune Deficiency Syndromes 51 (June 2009): 1. http://dx.doi.org/10.1097/01.qai.0000351094.48019.b6.

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Turci, Marco, Pierpaolo Racchiolli, Serena Ziglio, Dalila Astone, Almudena Blanco, and Donato Zipeto. "157a HLA-C Associates with Env and Increases HIV-1 Infectivity." JAIDS Journal of Acquired Immune Deficiency Syndromes 56 (April 2011): 65. http://dx.doi.org/10.1097/01.qai.0000397343.00180.17.

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Tam, Tran Thi Minh, Nguyen Thuy Linh, Phan Ha My, and Nguyen Thi Lan Anh. "Characteristics allelic of Human Leukocyte Antigen class I genotype and association with viral load and CD4 cell count in HIV-1 infected patients, Hanoi 2014 – 2016." Tạp chí Y học Dự phòng 31, no. 4 (June 18, 2021): 43–50. http://dx.doi.org/10.51403/0868-2836/2021/335.

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Human Leukocyte Antigen (HLA) class I plays a regulatory role in cellular immune response to HIV-1 infection. The role of HLA alleles in HIV progression via viral load and CD4 cell count is well known. HLA class I is polymorphic and distributed differently by nation. This descriptive cross-sectional study was performed on 303 HIV-1 infected patients in 2014 - 2016, with aims to (i) characterize HLA class I genotype with 4-digit nomenclature and (ii) identify specifc alleles in correlate with CD4 cell counts and HIV viral load. 117 allele genotypes have been identifed, including 28 HLA-A alleles, 54 HLA-B alleles and 35 HLA-C alleles. The results showed that the most prevalent alleles in the population include A*11:01 (30.7%), B*15:02 (15.2%) and C*08:01 (17.1%). The frequency of haplotype created from these alleles is 8.4%. A*02:03, B*46:01 related to gender and ethnicity respectively. In conclusion, the study provided detailed pattern of HLA class I expression in a study population of HIV-1 infected patients and reported for the frst time the associated B*51:01, C*14:02 alleles associated to an increase in CD4 cell counts.

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Yang, Hongbing, Margarida Rei, Simon Brackenridge, Elena Brenna, Hong Sun, Shaheed Abdulhaqq, Michael K. P. Liu, et al. "HLA-E–restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities." Science Immunology 6, no. 57 (March 25, 2021): eabg1703. http://dx.doi.org/10.1126/sciimmunol.abg1703.

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Human leukocyte antigen-E (HLA-E) normally presents an HLA class Ia signal peptide to the NKG2A/C-CD94 regulatory receptors on natural killer (NK) cells and T cell subsets. Rhesus macaques immunized with a cytomegalovirus-vectored simian immunodeficiency virus (SIV) vaccine generated Mamu-E (HLA-E homolog)–restricted T cell responses that mediated post-challenge SIV replication arrest in >50% of animals. However, HIV-1–specific, HLA-E–restricted T cells have not been observed in HIV-1–infected individuals. Here, HLA-E–restricted, HIV-1–specific CD8+ T cells were primed in vitro. These T cell clones and allogeneic CD8+ T cells transduced with their T cell receptors suppressed HIV-1 replication in CD4+ T cells in vitro. Vaccine induction of efficacious HLA-E–restricted HIV-1–specific T cells should therefore be possible.

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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, no. 16 (June 2, 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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Pai, Sara I., J. Jack Lee, Thomas E. Carey, William H. Westra, Soldano Ferrone, Charles Moore, Dong Moon Shin, and Robert L. Ferris. "Intact APM and PD-1:PD-L1 pathway upregulation in HIV-infected head and neck cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6058. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6058.

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6058 Background: HIV-infected individuals have a higher incidence of oral infection with human papillomavirus (HPV) and possibly a higher incidence of head and neck cancer (HNC). Whether this observation reflects defects in the ability of this Òimmune-compromisedÓ patient population to mount sufficient tumor specific immune responses and/or reflects activation of immune escape mechanisms is not known. To address this question, we investigated the expression of HLA class I antigen processing machinery (APM) components and PD-1:PD-L1 pathway activation in HIV(+) HNC patients. Methods: 62 HIV(+) HNC patients diagnosed between 1991-2011 from five tertiary care referral centers in the United States and matched HIV(-) HNC controls were identified. HLA class I APM component, PD-1, and PD-Ll expression were analyzed by immunohistochemical staining. Clinical data was abstracted from the medical records. Results: 44 of 62 (71%) HIV(+) HNC cases were matched based on gender, age ( < 10 years), and anatomic sub-site to HIV(-) HNC patients. There was no significant difference between the cases and controls in HLA-A, HLA-B/C, LMP2, and TAP1, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1. HLA-A, HLA-B/C, and LMP2 expression was significantly correlated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = 0.004, p = 0.026, and p = 0.006, respectively) but not in the HIV(-) controls. Similarly, HLA-A expression was also significantly associated with PD-L1 expression only in the HIV(+) HNC cases (p = 0.029). Conclusions: No defects were detected in the expression of the HLA class I APM components tested. PD-1:PD-L1 pathway was found to be upregulated in both HIV(+) and HIV(-) HNC patients. Our data suggest that recently approved anti-PD-1 immunotherapy should not exclude HIV(+) patients.

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Mann, Jaclyn K., Erasha Rajkoomar, Steven W. Jin, Qiniso Mkhize, Omolara Baiyegunhi, Pholisiwe Mbona, Mark A. Brockman, and Thumbi Ndung'u. "Consequences of HLA‐associated mutations in HIV‐1 subtype C Nef on HLA‐I downregulation ability." Journal of Medical Virology 92, no. 8 (February 7, 2020): 1182–90. http://dx.doi.org/10.1002/jmv.25676.

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Leslie, Alasdair, Philippa C. Matthews, Jennifer Listgarten, Jonathan M. Carlson, Carl Kadie, Thumbi Ndung'u, Christian Brander, et al. "Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection." Journal of Virology 84, no. 19 (July 21, 2010): 9879–88. http://dx.doi.org/10.1128/jvi.00320-10.

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ABSTRACT Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

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Dalal, Bhavik Ashok, Aruna Shankarkumar, and Amar Pazare. "MHC class I and II genes dependent hypersensitivity to nevirapine and efavirenz in Indian HIV-1 patients." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 177.11. http://dx.doi.org/10.4049/jimmunol.202.supp.177.11.

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Abstract OBJECTIVE The present study demonstrates and investigates the involvement of differences in human leukocyte antigens (HLA) class I and class II genes in the risk of hypersensitive reaction to nevirapine and efavirenz among Indian HIV- 1 infected patients. METHODS Thirty-three HIV-positive patients treated with efavirenz and nevirapine were studied. The HLA class I and II molecular typing in both Non-tolerant and tolerant patients were performed using the sequence-specific primers (SSP), the Olerup HLA-A-B-C and DQ-DR SSP Combi Tray. Odds ratios (OR) with 95 % confidence intervals (CI) were calculated to assess patients’ increased risk of developing hypersensitivity in comparison with Tolerant. RESULTS Thirteen patients (39.39%), developed a hypersensitive reaction thus requiring the drug to be discontinued. AnHLA-B*40 and HLA-C*15 allelesrevealed a significant association in 8/13 (61.53%) p = 0.028, OR= 9.6; 95% CI=1.04–222.49 and 7/13 (53.84%)p = 0.05, odds ratio (OR)= 8.75; 95% CI= 0.92–205.44 of hypersensitivity reaction in HIV patients compared with only 4% in Tolerant group, respectively. MHC class I genes, HLA-A*24 allele and MHC class II genes, DRB1*10:01:01:01 allele showed significant association with skin rash in 5/13 (38.46%) and 4/13 (30.76%) respectively (p<0.05). One patient developed potentially life-threatening condition i.e. Steven Johnson Syndrome. CONCLUSION A strong significant associations were seen between the MHC genes alleles (HLA-B*40 and HLA-C*15) and cART drug (nevirapine and efavirenz) induced skin rash in the Indian population. It can be utilized to avoid a subset of hypersensitivity reaction in HIV infected patients in Indian population.

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Mori, Masahiko, Ellen Leitman, Bruce Walker, Thumbi Ndung’u, Mary Carrington, and Philip Goulder. "Impact of HLA Allele-KIR Pairs on HIV Clinical Outcome in South Africa." Journal of Infectious Diseases 219, no. 9 (December 28, 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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Wright, Jaclyn K., Zabrina L. Brumme, Jonathan M. Carlson, David Heckerman, Carl M. Kadie, Chanson J. Brumme, Bingxia Wang, et al. "Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters." Journal of Virology 84, no. 20 (August 11, 2010): 10820–31. http://dx.doi.org/10.1128/jvi.01084-10.

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ABSTRACT The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B*81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B*81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B*81, significantly influence Gag-protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression.

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Porter, Kristen, Lauren Kelley, Michael Nekorchuk, James Jones, Amy Hahn, Carlos de Noronha, Jonathan Harton, and Karen Duus. "CIITA enhances HIV-1 attachment to CD4+ T cells leading to enhanced infection and cell depletion (154.27)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 154.27. http://dx.doi.org/10.4049/jimmunol.186.supp.154.27.

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Abstract Activated CD4+ T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4+ T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, resulting in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4+ T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4+ T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.

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Rousseau, Christine M., Marcus G. Daniels, Jonathan M. Carlson, Carl Kadie, Hayley Crawford, Andrew Prendergast, Philippa Matthews, et al. "HLA Class I-Driven Evolution of Human Immunodeficiency Virus Type 1 Subtype C Proteome: Immune Escape and Viral Load." Journal of Virology 82, no. 13 (April 23, 2008): 6434–46. http://dx.doi.org/10.1128/jvi.02455-07.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher's exact test; P ≤ 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (χ2; P = 3.59 × 10−5) and HLA-C (χ2; P = 4.71 × 10−6) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.

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Gong, XiaoYan, WeiWei Gai, JunQiang Xu, Wei Zhou, and Po Tien. "Glycoprotein 96-Mediated Presentation of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Human Leukocyte Antigen Class I-Restricted Peptide and Humoral Immune Responses to HIV-1 p24." Clinical and Vaccine Immunology 16, no. 11 (September 23, 2009): 1595–600. http://dx.doi.org/10.1128/cvi.00160-09.

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ABSTRACT Viral antigens complexed to heat shock proteins (HSPs) can enhance antiviral immunity. The present study evaluated the immunogenicity of a novel human immunodeficiency virus type 1B′ (HIV-1B′)-specific, human leukocyte antigen A2 (HLA-A2)-restricted peptide (FLQSRPEPTA, Gag448-457) and the cellular immune adjuvant effect of HSP gp96 using the HLA-A2 transgenic mouse model. It was found that gp96 could augment cytotoxic-T-lymphocyte responses specific for the 10-mer peptide of HIV-1B′. This study also evaluated the humoral immune adjuvant effect of HSP gp96 and its N-terminal fragment (N336) and found that immunization of BALB/c mice with a mixture of gp96 or its N-terminal fragment and HIV-1 p24 antigen or with an p24-N336 fusion protein resulted in a significant increase in anti-HIV p24 antibody titer. These results demonstrate the possibility of using gp96 and its N fragment as adjuvants to augment cellular and humoral immune responses against HIV-1 infection.

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DeGottardi, M. Quinn, Anke Specht, Benjamin Metcalf, Amitinder Kaur, Frank Kirchhoff, and David T. Evans. "Selective Downregulation of Rhesus Macaque and Sooty Mangabey Major Histocompatibility Complex Class I Molecules by Nef Alleles of Simian Immunodeficiency Virus and Human Immunodeficiency Virus Type 2." Journal of Virology 82, no. 6 (January 16, 2008): 3139–46. http://dx.doi.org/10.1128/jvi.02102-07.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Nef downregulates HLA-A and -B molecules, but not HLA-C or -E molecules, based on amino acid differences in their cytoplasmic domains to simultaneously evade cytotoxic T lymphocyte (CTL) and natural killer cell surveillance. Rhesus macaques and sooty mangabeys express orthologues of HLA-A, -B, and -E, but not HLA-C, and many of these molecules have unique amino acid differences in their cytoplasmic tails. We found that these differences also resulted in differential downregulation by primary simian immunodeficiency virus (SIV) SIVsmm/mac and HIV-2 Nef alleles. Thus, selective major histocompatibility complex class I downregulation is a conserved mechanism of immune evasion for pathogenic SIV infection of rhesus macaques and nonpathogenic SIV infection of sooty mangabeys.

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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, no. 10 (March 4, 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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Hadida, F., G. Haas, N. Zimmermann, A. Hosmalin, R. Spohn, A. Samri, G. Jung, P. Debre, and B. Autran. "CTLs from lymphoid organs recognize an optimal HLA-A2-restricted and HLA-B52-restricted nonapeptide and several epitopes in the C-terminal region of HIV-1 Nef." Journal of Immunology 154, no. 8 (April 15, 1995): 4174–86. http://dx.doi.org/10.4049/jimmunol.154.8.4174.

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Abstract In a previous analysis of HIV-1-specific CTLs in lymphoid organs from HIV-seropositive patients, we reported high frequencies of in vivo differentiated CTLs directed against two immunodominant regions in the central and in the C-terminal part of the HIV-1 Nef protein. The present study analyzes the epitopes recognized by CTLs in the carboxyl terminus of Nef (amino acids 182-205). In addition to several epitopes that are recognized in association with different HLA molecules (A1, A2, A25(10), B35, B52), we defined an optimal nonapeptide (190-198). This nonapeptide was recognized by CTLs down to nanomolar concentrations in the context of at least two HLA molecules, HLA-B52 and HLA-A2, including three HLA-A2 subtypes: HLA-A2.1, -A2.2, and -A2.4. We also determined the relative frequencies of effector CTLs directed against peptide 190-198 to be as high as 10(-4), as opposed to lower frequencies ranging between 5 x 10(-5) and 5 x 10(-6) observed for the other peptides recognized in the same region, thus confirming the optimal presentation of this nonapeptide in vivo. Molecular modeling of the interactions between HLA-A2.1 and Nef peptide 190-198 suggests the formation of a stable complex and allowed us to study sequence motifs that are important for the binding of the HIV-1 peptide in the pockets of the HLA-A2.1 molecule.

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Honeyborne, Isobella, Francisco M. Codoñer, Alasdair Leslie, Gareth Tudor-Williams, Graz Luzzi, Thumbi Ndung'u, Bruce D. Walker, Philip J. Goulder, and Julia G. Prado. "HLA-Cw*03-Restricted CD8+ T-Cell Responses Targeting the HIV-1 Gag Major Homology Region Drive Virus Immune Escape and Fitness Constraints Compensated for by Intracodon Variation." Journal of Virology 84, no. 21 (August 25, 2010): 11279–88. http://dx.doi.org/10.1128/jvi.01144-10.

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ABSTRACT The potential importance of HLA-C-restricted CD8+ cytotoxic T lymphocytes (CTL) in HIV infection remains undetermined. We studied the dominant HLA-Cw*03-restricted CTL response to YVDRFFKTL296-304 (YL9), within the conserved major homology region (MHR) of the Gag protein, in 80 HLA-Cw*03-positive individuals with chronic HIV infection to better define the efficacy of the YL9 HLA-C-restricted response. The HLA-Cw*03 allele is strongly associated with HIV sequence changes from Thr-303 to Val, Ile, or Ala at position 8 within the YL9 epitope (P = 1.62 × 10−10). In vitro studies revealed that introduction of the changes T303I and T303A into the YL9 epitope both significantly reduced CTL recognition and substantially reduced the viral replicative capacity. However, subsequent selection of the Val-303 variant, via intracodon variation from Ile-303 (I303V) or Ala-303 (A303V), restored both viral fitness and CTL recognition, as supported by our in vivo data. These results illustrate that HLA-C-restricted CTL responses are capable of driving viral immune escape within Gag, but in contrast to what was previously described for HLA-B-restricted Gag escape mutants, the common Cw*03-Gag-303V variant selected resulted in no detectable benefit to the host.

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Mkhwanazi, Nompumelelo, Christina F. Thobakgale, Mary van der Stok, Shabashini Reddy, Zenele Mncube, Fundisiwe Chonco, Bruce D. Walker, Marcus Altfeld, Philip J. R. Goulder, and Thumbi Ndung'u. "Immunodominant HIV-1-specific HLA-B- and HLA-C-restricted CD8+ T cells do not differ in polyfunctionality." Virology 405, no. 2 (September 2010): 483–91. http://dx.doi.org/10.1016/j.virol.2010.06.002.

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Hu, Qinxue, Ines Frank, Vennansha Williams, John J. Santos, Patricia Watts, George E. Griffin, John P. Moore, Melissa Pope, and Robin J. Shattock. "Blockade of Attachment and Fusion Receptors Inhibits HIV-1 Infection of Human Cervical Tissue." Journal of Experimental Medicine 199, no. 8 (April 12, 2004): 1065–75. http://dx.doi.org/10.1084/jem.20022212.

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Identification of cellular factors involved in HIV-1 entry and transmission at mucosal surfaces is critical for understanding viral pathogenesis and development of effective prevention strategies. Here we describe the evaluation of HIV-1 entry inhibitors for their ability to prevent infection of, and dissemination from, human cervical tissue ex vivo. Blockade of CD4 alone or CCR5 and CXCR4 together inhibited localized mucosal infection. However, simultaneous blockade of CD4 and mannose-binding C-type lectin receptors including dendritic cell–specific intercellular adhesion molecule–grabbing integrin was required to inhibit HIV-1 uptake and dissemination by migratory cells. In contrast, direct targeting of HIV-1 by neutralizing mAb b12 and CD4-IgG2 (PRO-542) blocked both localized infection and viral dissemination pathways. Flow cytometric analysis and immunostaining of migratory cells revealed two major populations, CD3+HLA-DR− and CD3−HLA-DR+ cells, with a significant proportion of the latter also expressing dendritic cell–specific intercellular adhesion molecule–grabbing integrin. Bead depletion studies demonstrated that such HLA-DR+ cells accounted for as much as 90% of HIV-1 dissemination. Additional studies using immature monocyte-derived dendritic cells demonstrated that although mannose-binding C-type lectin receptors and CD4 are the principal receptors for gp120, other mechanisms may account for virus capture. Our identification of the predominant receptors involved in HIV-1 infection and dissemination within human cervical tissue highlight important targets for microbicide development.

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Koofhethile, Catherine K., Zaza M. Ndhlovu, Christina Thobakgale-Tshabalala, Julia G. Prado, Nasreen Ismail, Zenele Mncube, Lungile Mkhize, et al. "CD8+T Cell Breadth andEx VivoVirus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles." Journal of Virology 90, no. 15 (May 18, 2016): 6818–31. http://dx.doi.org/10.1128/jvi.00276-16.

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ABSTRACTThe mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P= 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8+T cell responses against Gag and enhanced ability of CD8+T cells to suppress viral replicationex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8+T cell responses in the absence of differences in HIV-1-specific CD8+T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8+T cell responses characterized by reduced ability to suppress viral replicationex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8+T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8+T cell-independent mechanisms.IMPORTANCEHost mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8+T cells that targeted the Gag protein, and CD8+T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8+T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.

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Crawford, Hayley, Wendy Lumm, Alasdair Leslie, Malinda Schaefer, Debrah Boeras, Julia G. Prado, Jianming Tang, et al. "Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients." Journal of Experimental Medicine 206, no. 4 (March 23, 2009): 909–21. http://dx.doi.org/10.1084/jem.20081984.

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HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

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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, no. 2 (January 15, 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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McLaren, Paul J., Cedric Coulonges, István Bartha, Tobias L. Lenz, Aaron J. Deutsch, Arman Bashirova, Susan Buchbinder, et al. "Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load." Proceedings of the National Academy of Sciences 112, no. 47 (November 9, 2015): 14658–63. http://dx.doi.org/10.1073/pnas.1514867112.

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Previous genome-wide association studies (GWAS) of HIV-1–infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation—mostly in the HLA and CCR5 regions—explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

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Geels, Mark J., Sheri A. Dubey, Kiersten Anderson, Elly Baan, Margreet Bakker, Georgios Pollakis, William A. Paxton, John W. Shiver, and Jaap Goudsmit. "Broad Cross-Clade T-Cell Responses to Gag in Individuals Infected with Human Immunodeficiency Virus Type 1 Non-B Clades (A to G): Importance of HLA Anchor Residue Conservation." Journal of Virology 79, no. 17 (September 1, 2005): 11247–58. http://dx.doi.org/10.1128/jvi.79.17.11247-11258.2005.

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ABSTRACT We aimed to identify cross-clade human immunodeficiency virus type 1 (HIV-1) specific T-cell responses among 10 HLA-typed individuals who were infected with non-B HIV-1 strains (A, AG, C, D, G, or F) and to correlate these responses with genetic variation in documented T-cell epitopes. T-cell reactivity was tested against peptide pools spanning clade B Gag, Pol, Nef, Rev, and Tat consensus, with Gag and Nef providing the highest responses. Nine individuals who responded to clade B Gag demonstrated cross-reactive T-cell responses against clade A and C Gag pools, while six of seven responders to Nef-B reacted to clade A and C Nef pools. An inverse correlation between the height of the T-cell responses and the sequence divergence of the HLA class I-restricted epitopes was identified when we compared autologous Gag and Nef sequences with the reactive consensus pools. This could be explained for the Gag sequences through observed variations in the HLA anchor residues. Through mapping of 30 amino acid cross-clade-reactive regions using Gag-B pools, we were able to link 58% (14/24) of the T-cell responses to regions containing previously described HLA class I-restricted epitopes. Forty-two percent (10/24) of the responses were directed to regions containing new epitopes, for which predicted HLA class I motifs could be recognized in 70% (7/10) of individuals. We demonstrate here that cross-clade T-cell responses are frequently induced in individuals infected with distinct HIV-1 clades, suggesting that interclade variation outside of HLA anchor residues may have less impact on vaccine-induced T-cell reactivity than previously thought.

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Ziglio, Serena, Dalila Astone, Giulia Danesin, Pierpaolo Racchiolli, Almudena Blanco, and Donato Zipeto. "C4 Association Analysis Between HIV-1 Env and HLA-C Using Bimolecular Fluorescence Complementation." JAIDS Journal of Acquired Immune Deficiency Syndromes 59 (April 2012): 78. http://dx.doi.org/10.1097/01.qai.0000413799.87274.a3.

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Celsi, Fulvio, Eulalia Catamo, Giulio Kleiner, Paola Maura Tricarico, Josef Vuch, and 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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Tang, Jianming, Shenghui Tang, Elena Lobashevsky, Angela D. Myracle, Ulgen Fideli, Grace Aldrovandi, Susan Allen, Rosemary Musonda, and Richard A. Kaslow. "Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1." Journal of Virology 76, no. 16 (August 15, 2002): 8276–84. http://dx.doi.org/10.1128/jvi.76.16.8276-8284.2002.

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ABSTRACT The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8+ cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log10 VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log10 VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.

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Santos-Pereira, Ana, Vera Triunfante, Pedro M. M. Araújo, Joana Martins, Helena Soares, Eva Poveda, Bernardino Souto, and Nuno S. Osório. "Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil." International Journal of Molecular Sciences 22, no. 10 (May 18, 2021): 5304. http://dx.doi.org/10.3390/ijms22105304.

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The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008–2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.

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Yu, Xu G., Mathias Lichterfeld, Senica Chetty, Katie L. Williams, Stanley K. Mui, Toshiyuki Miura, Nicole Frahm, et al. "Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes." Journal of Virology 81, no. 4 (November 22, 2006): 1619–31. http://dx.doi.org/10.1128/jvi.01580-06.

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ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703+ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

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Matthews, Philippa C., Andrew Prendergast, Alasdair Leslie, Hayley Crawford, Rebecca Payne, Christine Rousseau, Morgane Rolland, et al. "Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point." Journal of Virology 82, no. 17 (July 2, 2008): 8548–59. http://dx.doi.org/10.1128/jvi.00580-08.

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ABSTRACT Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = −0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = −0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.

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Saravanan, Shanmugam, Vidya Madhavan, Kailapuri G. Murugavel, Pachamuthu Balakrishnan, Sunil Suhas Solomon, Shankarkumar Umapathy, Rami Kantor, et al. "The Association between HIV-1 Subtype C Antiretroviral Resistance and HLA Prevalence in Southern India." JAIDS Journal of Acquired Immune Deficiency Syndromes 57, no. 1 (May 2011): e17-e19. http://dx.doi.org/10.1097/qai.0b013e3182169050.

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Ruiz, Alba, Ester Ballana, Beatriz Mothe, Eulalia Grau, Bonaventura Clotet, Christian Brander, and José A. Esté. "HLA-C-35C/T Variant: Genetic Association to HIV-1 Disease Progression and Functional Links." Antiviral Research 90, no. 2 (May 2011): A41—A42. http://dx.doi.org/10.1016/j.antiviral.2011.03.063.

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Kozlowska, A., W. Gorczyca, Z. Mackiewicz, I. Wojciechowska, and P. Kusnierczyk. "Octapeptide but not nonapeptide from HIV-1 p24gag protein upregulates cell surface HLA-C expression." HIV Medicine 1, no. 4 (October 2000): 200–204. http://dx.doi.org/10.1046/j.1468-1293.2000.00029.x.

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Journal articles on the topic 'HIV-1, HLA-C'

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