HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses

PLoS Pathogens

Victor Y. Du¹  Sonya Heath¹  Anju Bansal¹  Sarah Sterrett¹  Jianming Tang¹  Alexander Jureka¹  Paul A. Goepfert¹  Nathan Erdmann¹  Ling Yue²  Malinda Schaefer²  Dario Dilernia²  Susan Allen²  Eric Hunter²  Jill Gilmour³  John Sidney⁴  Jonathan Carlson⁵  Shabir Lakhi⁶ 

[1] Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;International AIDS Vaccine Institute and Imperial College, London, United Kingdom;La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America;Microsoft Research, Los Angeles, California, United States of America;Zambia Emory Research Project, Lusaka, Zambia

关键词: T cells;    HIV;    Enzyme-linked immunoassays;    Antigens;    HIV-1;    Cytotoxic T cells;    Alleles;    Immune response;   

DOI  :  10.1371/journal.ppat.1005111

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY