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Relationship between HLA Genotype and the functional profile of Antigen-specific CD8 T cells

Harari, A., Cellerai, C., Kostler, J., Gaudieri, S., James, I., John, M., Wagner, R., Mallal, S. and Pantaleo, G. (2007) Relationship between HLA Genotype and the functional profile of Antigen-specific CD8 T cells. In: 14th Conference on Retroviruses and Opportunistic Infections, 25 - 28 February 2007, Los Angeles, U.S.A.

Abstract

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.

Publication Type: Conference Item
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Conference Website: http://www.retroconference.org/2007/
Notes: Oral presentation
URI: http://researchrepository.murdoch.edu.au/id/eprint/15715
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