title: HIV Controllers Exhibit Enhanced Frequencies of Major Histocompatibility Complex Class II Tetramer+Gag-Specific CD4+T Cells in Chronic Clade C HIV-1 Infection.
abstract: Immune control of viral infections is heavily dependent on helper CD4+T cell function. However, the understanding of the contribution of HIV-specific CD4+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+T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4+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+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+T cells in HIV controllers than progressors (P= 0.0001), and these expanded Gag-specific CD4+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 (r= -0.5,P= 0.02). These data identify an association between HIV-specific CD4+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+T cell responses in natural infections.IMPORTANCEIncreasing evidence suggests that virus-specific CD4+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+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+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+T cell responses in HIV-1 clade C infection. Our results demonstrate an association between the frequency of HIV-specific CD4+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.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Faatima
authors.initials: F
authors.lastname: Laher
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Srinika
authors.initials: S
authors.lastname: Ranasinghe
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Filippos
authors.initials: F
authors.lastname: Porichis
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Nikoshia
authors.initials: N
authors.lastname: Mewalal
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Karyn
authors.initials: K
authors.lastname: Pretorius
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Nasreen
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.|Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.|KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa zndhlovu@mgh.harvard.edu.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Zaza M
authors.initials: ZM
authors.lastname: Ndhlovu
mesh_terms: D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018450:Disease Progression; D060467:Disease Resistance; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D008297:Male; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: CD4 T helper cells; MHC class II tetramers; human immunodeficiency virus, HIV