11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11; 11:(abstract no. 16)

M Lichterfeld, X G Yu, D Kaufmann, S Mui, N Johnston, D Cohen, M M Addo, D Strick, E S Rosenberg, B D Walker, and M Altfeld
Massachusetts Gen. Hosp., Harvard Med. Sch., Boston, MA, USA

BACKGROUND: HIV-1-specific CD8⁺ T cells play a crucial role for the spontaneous control of HIV-1 replication, yet, in numerous studies, no correlation was found between HIV-specific CD8⁺ T-cell responses in interferon-γ ELISpot and clinical or surrogate markers of HIV disease progression, even when comprehensive screening approaches were applied. Thus, it is currently unclear if interferon-γ secretion by HIV-specific CD8⁺ T cells adequately reflects their ability to eliminate HIV-infected cells by MHC-class I restricted cytolysis.

METHODS: Here, we adapted a novel cytotoxicity assay based on caspase-3 substrates as indicators of target cell death, allowing for the direct ex vivo measurement of the cytolytic capacity of HIV-specific CD8⁺ T cells. Using this method, we directly compared interferon-γ secretion, as determined by intracellular cytokine staining, with the cytotoxic capacity of freshly-isolated HIV-specific CD8⁺ T cells.

RESULTS: In a total of 48 different HIV-specific CD8⁺ T-cell populations from 8 different study subjects, we found considerable intra-individual and inter-individual differences between cytotoxic- and IFN-γ-secreting responses to individuals epitopes, indicating that the execution of these effector functions is only weakly correlated (R=0.46, p=0.0015). A substantially stronger relationship (R=0.65, p<0.0001) was found when the cytotoxic potential of CD8⁺ T cells was plotted against the proportion of HIV-specific CD8⁺ T cells that produced both TNF-α and interferon-γ following viral stimulation. In contrast, no correlation was found between the cytotoxic potential of HIV-specific CD8⁺ T cells and the proportion of cells that produce interferon-γ but no TNF-α following viral stimulation (R=0.3, p=0.4).

CONCLUSION: These results suggest that the direct cytolytic effects of HIV-specific CD8⁺ T cells are preferentially mediated by the subset of cells capable of producing both interferon-γ and TNF-α in response to viral stimulation. The characterization of this CD8⁺ T cell subset will be thus relevant for a more precise evaluation of CD8⁺ T cell mediated HIV-specific immune responses generated naturally or following immunization with HIV vaccine candidates.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.