title: HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.
abstract: Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences and HLA-II allelic data, we identified 29 HLA-II associated HIV sequence polymorphisms or adaptations (HLA-AP) in an African cohort of chronically HIV-infected individuals. Epitopes encompassing the predicted adaptation (AE) or its non-adapted (NAE) version were evaluated for immunogenicity. Using a CD8-depleted IFN-γ ELISpot assay, we determined that the magnitude of CD4+ T cell responses to the predicted epitopes in controllers was higher compared to non-controllers (p<0.0001). However, regardless of the group, the magnitude of responses to AE was lower as compared to NAE (p<0.0001). CD4+ T cell responses in patients with acute HIV infection (AHI) demonstrated poor immunogenicity towards AE as compared to NAE encoded by their transmitted founder virus. Longitudinal data in AHI off antiretroviral therapy demonstrated sequence changes that were biologically confirmed to represent CD4+ escape mutations. These data demonstrate an innovative application of HLA-associated polymorphisms to identify biologically relevant CD4+ epitopes and suggests CD4+ T cells are active participants in driving HIV evolution.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Nathan
authors: N
authors: Erdmann
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Victor Y
authors: VY
authors: Du
authors: Microsoft Research, Los Angeles, California, United States of America.
authors: Jonathan
authors: J
authors: Carlson
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors: Malinda
authors: M
authors: Schaefer
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Alexander
authors: A
authors: Jureka
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Sarah
authors: S
authors: Sterrett
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors: Ling
authors: L
authors: Yue
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors: Dario
authors: D
authors: Dilernia
authors: Zambia Emory Research Project, Lusaka, Zambia.
authors: Shabir
authors: S
authors: Lakhi
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Jianming
authors: J
authors: Tang
authors: La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.
authors: John
authors: J
authors: Sidney
authors: International AIDS Vaccine Institute and Imperial College, London, United Kingdom.
authors: Jill
authors: J
authors: Gilmour
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors: Susan
authors: S
authors: Allen
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors: Eric
authors: E
authors: Hunter
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Sonya
authors: S
authors: Heath
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Anju
authors: A
authors: Bansal
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Paul A
authors: PA
authors: Goepfert
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D005434:Flow Cytometry; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics* / Q000276:immunology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II