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Relationship between HLA Genotype and the Functional Profile of Antigen-specific CD8 T Cells
Alexandre Harari*1, C Cellerai1, J Kostler2, S Gaudieri3, I James3, M John3, R Wagner2, S Mallal3, and G Pantaleo1
1Ctr Hosp Univ Vaudois Lausanne, Switzerland; 2Univ Regensburg, Germany; and 3Ctr for Clinical Immunology and Biomed Stats, Royal Perth Hosp, Murdoch Univ, Australia
Background: Polyfunctional
(interferon-gamma [IFN-γ] and interleukin-2 [IL-2] secretion and
proliferation) and not monofunctional (IFN-γ secretion) CD8 T-cell
responses are associated with protective antiviral immunity and nonprogressive
HIV disease. On the other hand, HLA-B influences the outcome of HIV disease. In
this study, we have investigated the relationship between the HLA genotype and
the functional profile of CD8 T cells.
Methods: We performed a comprehensive characterization
of HLA genotype (4-digit) and of the functional profile of virus-specific CD8
T-cell responses against HIV-1, cytomegalovirus (CMV), Epstein-Barr virus
(EBV), and influenza (flu) in 177 subjects comprising 69 HIV–, 99
subjects with chronic progressive HIV-1 infection, and 9 long-term nonprogressors (LTNP).
Results: Gag (n
= 89) responses, obtained from 44 experimentally confirmed peptide-HLA
associations, were identified and characterized in HIV-1-infected progressors.
HLA-B-restricted epitopes were associated more
frequently with polyfunctional CD8 T-cell responses than HLA-A-restricted epitopes (p =
0.008). In addition, in a panel of 13 responses derived from gag epitopes restricted either by HLA-A
or HLA-B alleles, polyfunctional CD8 T-cell responses were associated with HLA-B-restriction
(p = 0.002). Of note, monofunctional
HLA-A-restricted and polyfunctional HLA-B-restricted
responses were simultaneously observed within the same subjects. Furthermore,
HIV-1- (in LTNP), EBV-, CMV-, and flu-derived HLA-B-restricted responses were
significantly more polyfunctional than HLA-A-restricted responses (p = 0.03, 0.02, 0.02, and 0.005,
respectively). Of interest, HLA-B-restricted responses were associated with
lower avidity, lower differentiation state, and lower PD-1 level of expression
as compared with HLA-A-restricted responses (p = 0.004, 0.004, 0.008, respectively). Finally, a significant
correlation was observed between PD-1 expression and the proportion of
HIV-1-specific IL-2 secreting CD8 T cells (p
<0.001).
Conclusions: These results provide new insights into the
associations between HLA restriction, TCR avidity, PD-1 expression, and the
functional profile of virus-specific CD8 T-cell responses.
Furthermore,
they provide the rationale for the protective role of HLA-B in HIV-1 infection.
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