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Immunodomination by HLA-B27- and HLA-B57-restricted HIV-1-specific T-cell Responses Results in Abrogation of other HLA-restricted Responses in Primary HIV-1 Infection
Hendrik Streeck*1, G Alter1, N Teigen1, M Swartz1, R P Sekaly2, A Kelleher3, S Little4, T Allen1, B Walker1, and M Altfeld1
1Partners AIDS Res Ctr, Massachusetts Gen Hosp, Harvard Med Sch, Boston, US; 2Ctr Hosp Univ Montreal, Canada; 3Ctr for Immunology, St Vincent's Hosp, Darlinghurst, Australia; and 4Antiviral Res Ctr, Univ of California, San Diego, US
Background: Immunodomination describes the ability of dominant HLA-restricted cytotoxic T lymphocyte (CTL) responses to suppress the
generation of other responses, and is highly relevant for vaccine design. To
identify dominating HIV-1-specific CD8+ T cell epitopes
in HIV-1 infection, we characterized the immunodominance
patterns of CD8+ T-cell responses in a large cohort of subjects with
primary HIV-1 infection.
Methods: In 293 subjects with primary HIV-1 infection,
HIV-1-specific CTL responses were quantified by interferon-gamma (IFN-g) ELISpot, using a panel of 268
peptides corresponding to previously described HLA-matched optimal clade B CTL epitopes.
Results: HLA-B-restricted CTL responses contributed significantly to
the total early HIV-1-specific CTL response compared to HLA-A–
(41%±2 vs 49%±2; p
= 0.007) or HLA-Cw-restricted (11%±1, p <0.0001) responses. However, HLA-B
dominance was largely attributable to the dominant effect of HLA-B27/B57, as
differences in the total contribution of HLA-A–and HLA-B-restricted
CD8+ T-cell responses were not significant in the absence of
HLA-B57/-B27 (p = 0.3). We identified
37 individuals expressing HLA-B57/B27 and compared responses restricted by
these 2 alleles to those restricted by all other co-expressed HLA alleles. In
the 256 individuals not expressing HLA-B57/27, HIV-1-specific CD8+
T-cell responses restricted by HLA-A (44%), all B alleles (43%), or individual
common HLA-B molecules (B7 = 32%, B8 = 34%, B35 = 31%) contributed importantly
to the total virus-specific T-cell response. In contrast, the presence of
HLA-B57 or B27 significantly abrogated the frequency and magnitude of responses
restricted by these other alleles (grouped HLA-A
alleles: 18%±5 p <0.0001; grouped
B alleles: 7%±4 p <0.0001; HLA-B7: 0.5%±0.5
p = 0.02; B8: 5%±4 p
= 0.03; B35: 0%±0 p <0.001).
Conclusions: These data demonstrate that the evolution of HIV-1-specific
CD8+ T-cell responses restricted by HLA-A and B alleles is
significantly suppressed by the presence of HLA-B27- and HLA-B57-restricted
responses during primary HIV-1 infection. Our data in a large cohort of
subjects with primary infection also suggest that the combination of different
HLA class I alleles, and not the presence of an individual allele, determines
the immunodominance patterns of CD8+
T-cell responses during primary HIV-1 infection.
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