Immunodominant HIV-1 Cd4+ T cell epitopes in chronic untreated clade C HIV-1 infection.
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.


RESULTS
Intracellular cytokine staining was conducted on 373 subjects with chronic, untreated clade C infection to assess interferon-gamma (IFN-gamma) responses by CD4+ T cells to pooled Gag peptides and to determine their association with viral load and CD4 count. Gag-specific IFN-gamma-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
These data indicate that in chronic untreated clade C HIV-1 infection, IFN-gamma-secreting Gag-specific CD4+ T cell responses are immunodominant, directed at multiple distinct epitopes, and associated with viral control.
Ramduth
Danni
D
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. dramduth@gmail.com
Day
Cheryl L
CL
Thobakgale
Christina F
CF
Mkhwanazi
Nompumelelo P
NP
de Pierres
Chantal
C
Reddy
Sharon
S
van der Stok
Mary
M
Mncube
Zenele
Z
Nair
Kriebashne
K
Moodley
Eshia S
ES
Kaufmann
Daniel E
DE
Streeck
Hendrik
H
Coovadia
Hoosen M
HM
Kiepiela
Photini
P
Goulder
Philip J R
PJ
Walker
Bruce D
BD
D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008969:Molecular Sequence Data; D019562:Viral Load
D016056:Immunodominant Epitopes; D007371:Interferon-gamma