{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:45:54Z","timestamp":1790660754856,"version":"4.1.0"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Immune control of viral infections is heavily dependent on helper CD4<jats:sup>+<\/jats:sup>T cell function. However, the understanding of the contribution of HIV-specific CD4<jats:sup>+<\/jats:sup>T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4<jats:sup>+<\/jats:sup>T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4<jats:sup>+<\/jats:sup>T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4<jats:sup>+<\/jats:sup>T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4<jats:sup>+<\/jats:sup>T cells in HIV controllers than progressors (<jats:italic>P<\/jats:italic>= 0.0001), and these expanded Gag-specific CD4<jats:sup>+<\/jats:sup>T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control (<jats:italic>r<\/jats:italic>= \u22120.5,<jats:italic>P<\/jats:italic>= 0.02). These data identify an association between HIV-specific CD4<jats:sup>+<\/jats:sup>T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4<jats:sup>+<\/jats:sup>T cell responses in natural infections.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Increasing evidence suggests that virus-specific CD4<jats:sup>+<\/jats:sup>T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4<jats:sup>+<\/jats:sup>T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV infections worldwide. Understanding the contribution of HIV-specific CD4<jats:sup>+<\/jats:sup>T cell responses in clade C infection is particularly important for developing vaccines that would be efficacious in sub-Saharan Africa, where clade C infection is dominant. Here, we employed MHC class II tetramers designed to immunodominant Gag epitopes and used them to characterize CD4<jats:sup>+<\/jats:sup>T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4<jats:sup>+<\/jats:sup>T cell responses targeting an immunodominant DRB1*11-Gag41 complex and HIV control, highlighting the important contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infections.<\/jats:p>","DOI":"10.1128\/jvi.02477-16","type":"journal-article","created":{"date-parts":[[2017,1,12]],"date-time":"2017-01-12T02:32:08Z","timestamp":1484188328000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer<sup>+<\/sup>Gag-Specific CD4<sup>+<\/sup>T Cells in Chronic Clade C HIV-1 Infection"],"prefix":"10.1128","volume":"91","author":[{"given":"Faatima","family":"Laher","sequence":"first","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinika","family":"Ranasinghe","sequence":"additional","affiliation":[{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA"},{"name":"Center for HIV\/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippos","family":"Porichis","sequence":"additional","affiliation":[{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA"},{"name":"Center for HIV\/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikoshia","family":"Mewalal","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karyn","family":"Pretorius","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasreen","family":"Ismail","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Buus","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anette","family":"Stryhn","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Carrington","sequence":"additional","affiliation":[{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA"},{"name":"Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Walker","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"},{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA"},{"name":"Howard Hughes Medical Institute, Chevy Chase, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thumbi","family":"Ndung'u","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"},{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA"},{"name":"KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa"},{"name":"Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaza M.","family":"Ndhlovu","sequence":"additional","affiliation":[{"name":"HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. 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