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

• Type of Material: Article
• Authors: Nathan Erdmann, University of Alabama; Victor Y. Du, University of Alabama; Jonathan Carlson, Microsoft Research; Malinda Schaefer, Emory University; Alexander Jureka, University of Alabama; Sarah Sterrett, University of Alabama; Dario Dilernia, Emory University; Shabir Lakhi, Zambia Emory Research Project; Jianming Tang, University of Alabama; John Sidney, La Jolla Institute for Allergy & Immunology; Jill Gilmour, International AIDS Vaccine Institute and Imperial College; Susan Allen, Emory University; Eric Hunter, Emory University; Ling Yue, Emory University; Sonya Heath, University of Alabama; Anju Bansal, University of Alabama; Paul A. Goepfert, University of Alabama
• Language: English
• Date: 2015-01-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Erdmann et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1005111
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 11
• Issue: 8
• Start Page: e1005111
• End Page: e1005111
• Grant/Funding Information: This work was supported by these NIH grants: 5R01AI084772-05, 1R01AI112566-01A1, and 5R01AI064060-10.
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

Abstract

© 2015 Erdmann et al. 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.