Ramduth, DanniDay, Cheryl L.Thobakgale, Christina F.Mkhwanazi, Nompumelelo P.de Pierres, ChantalReddy, Sharonvan der Stok, MaryMncube, ZeneleNair, KriebashneMoodley, Eshia S.Coovadia, Hoosen M.Kiepiela, PhotiniKaufmann, Daniel E.Streeck, HendrikGoulder, Philip J.Walker, Bruce2011-05-132009Ramduth, Danni, Cheryl L. Day, Christina F. Thobakgale, Nompumelelo P. Mkhwanazi, Chantal de Pierres, Sharon Reddy, Mary van der Stok, et al. 2009. Immunodominant HIV-1 Cd4+ T Cell Epitopes in Chronic Untreated Clade C HIV-1 Infection. PLoS ONE 4(4): e5013.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:4889439Background: 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-γ) 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.en-USinfectious diseasesimmunologyantigen processing and recognitionHIV infection and AIDSJournal Article2011-05-1310.1371/journal.pone.0005013