A new paper from Bruce Walker’s group follows up on their
prior work regarding the importance of Gag-specific CD8 T cell responses by
evaluating Gag-specific CD4 T cells in chronic clade C HIV infection. The study
found that the presence of Gag-specific CD4 T cells (as measured solely by
interferon gamma production) was associated with significantly lower viral load
on average compared to participants lacking these responses (29,900 copies vs. 91,900
copies). However, there was considerable overlap between the two groups, as
would be expected given that previous studies have found that the magnitude of HIV-specific CD4 T
cell responses measured by interferon gamma production does not correlate with
control of viral load.
To compare CD4 T cell responses to Gag with those targeting
other HIV antigens, 32 randomly selected participants were screened for CD4 T
cell responses to a pool of peptides (protein fragments) derived from all clade
C HIV proteins. This analysis revealed 33 peptides targeted by CD4 T cells, and
27 of the 33 were located in Gag. On average, responses to Gag made up at least
50% of the total HIV-specific CD4 T cell response among study participants.
The researchers also found that while the magnitude of the
total HIV-specific CD4 T cell response did not correlate with viral load, there
was a significant inverse correlation with the breadth of the response (i.e.
targeting of more peptides was associated with lower viral loads). When
responses to just Gag were analyzed, there were significant correlations
between both the number of peptides targeted and the magnitude of the response
and viral load; broader and stronger Gag-specific CD4 T cell responses were
associated with lower viral load.
The authors of the paper emphasize that it will be important
to verify these results in larger cohorts and also look in more detail at
production of other cytokines as well as interferon gamma. They also note the important caveat that some of the bias toward Gag is likely explained by the relative conservation of this protein; since the T cell assays use peptides based on the most common circulating viruses (consensus peptides), there may be responses present to variant peptides from other less conserved proteins that the assays can't detect. But, even with these caveats, the data represent another addition to the growing literature on the potential contribution to viral
load control of broad T cell responses targeting Gag. Unfortunately, to date, HIV
vaccine candidates have abjectly failed to induce T cell responses to multiple epitopes
within the Gag protein.
PLoS ONE. 2009;4(4):e5013. Epub 2009 Apr 7.
Immunodominant HIV-1 CD4+ T cell epitopes in chronic
untreated clade C HIV-1 infection.
Ramduth D, Day CL, Thobakgale CF, Mkhwanazi NP, de Pierres
C, Reddy S, van der Stok M, Mncube Z, Nair K, Moodley ES, Kaufmann DE, Streeck
H, Coovadia HM, Kiepiela P, Goulder PJ, Walker BD.
HIV Pathogenesis Programme, Doris Duke Medical Research
Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal,
Durban, South Africa. dramduth@gmail.com
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-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/SIGNIFICANCE:
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.
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