14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 24)

Alexandre Harari¹, C Cellerai¹, J Kostler², S Gaudieri³, I James³, M John³, R Wagner², S Mallal³, and G Pantaleo^1
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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2007-02-25
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