Immunodominant HIV-1 Cd4+T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection

• Type of Material: Article
• Authors: Danni Ramduth, University of Kwazulu Natal; Cheryl Day, Emory University; Christina F. Thobakgale, University of Kwazulu Natal; Nompumelelo P. Mkhwanazi, University of Kwazulu Natal; Chantal de Pierres, University of Kwazulu Natal; Sharon Reddy, University of Kwazulu Natal; Mary van der Stok, University of Kwazulu Natal; Zenele Mncube, University of Kwazulu Natal; Kriebashne Nair, University of Kwazulu Natal; Eshia S. Moodley, University of Kwazulu Natal; Daniel E. Kaufmann, Harvard University; Hendrik Streeck, Harvard University; Hoosen M. Coovadia, University of Kwazulu Natal; Photini Kiepiela, University of Kwazulu Natal; Philip J. R. Goulder, University of Kwazulu Natal; Bruce D. Walker, University of Kwazulu Natal
• Language: English
• Date: 2009-04-07
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2009 Ramduth et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0005013
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 4
• Issue: 4
• Start Page: e5013
• End Page: e5013
• Grant/Funding Information: This study was funded by the US National Institute of Health (Contract N01-A1-15422, 2 RO1AI46995-06, and RO1AI067073).
• Keywords: Multidisciplinary Sciences; Science & Technology; Science & Technology - Other Topics
• Research Categories: Health Sciences, Immunology

Abstract

Background: A dominance of Gag-specific CD8+ T cell responses is significantly associated with a lower viral load in individuals with chronic, untreated clade C human immunodeficiency virus type 1 (HIV-1) infection. This association has not been investigated in terms of Gag-specific CD4+ T cell responses, nor have clade C HIV-1-specific CD4+ T cell epitopes, likely a vital component of an effective global HIV-1 vaccine, been identified. Methodology/Principal Findings: Intracellular cytokine staining was conducted on 373 subjects with chronic, untreated clade C infection to assess interferon-gamma (IFN-c) responses by CD4+ T cells to pooled Gag peptides and to determine their association with viral load and CD4 count. Gag-specific IFN-γ-producing CD4+ T cell responses were detected in 261/373 (70%) subjects, with the Gag responders having a significantly lower viral load and higher CD4 count than those with no detectable Gag response (p<0.0001 for both parameters). To identify individual peptides targeted by HIV-1-specific CD4+ T cells, separate ELISPOT screening was conducted on CD8-depleted PBMCs from 32 chronically infected untreated subjects, using pools of overlapping peptides that spanned the entire HIV-1 clade C consensus sequence, and reconfirmed by flow cytometry to be CD4+ mediated. The ELISPOT screening identified 33 CD4+ peptides targeted by 18/32 patients (56%), with 27 of the 33 peptides located in the Gag region. Although the breadth of the CD4+ responses correlated inversely with viral load (p = 0.015), the magnitude of the response was not significantly associated with viral load. Conclusions/Significance: These data indicate that in chronic untreated clade C HIV-1 infection, IFN-γ-secreting Gag-specific CD4+ T cell responses are immunodominant, directed at multiple distinct epitopes, and associated with viral control.