AEGiS-15IAC: The cytotoxic activity of HIV-1-specific CD8+ T cells is preferentially mediated by the subset of cells secreting both interferon-g and TNF-a following viral stimulation.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

The cytotoxic activity of HIV-1-specific CD8+ T cells is preferentially mediated by the subset of cells secreting both interferon-g and TNF-a following viral stimulation.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1051)

Lichterfeld M, Yu XG, Mui S, Johnston M, Cohen D, Strick D, Rosenberg E, Walker BD, Altfeld M
Partners AIDS Research Center, Massachusetts General Hospital, Boston, United States

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-g Elispots and markers of HIV disease progression. Thus, it is currently unclear if interferon-g secretion by HIV-specific CD8+ T cells adequately reflects their ability to directly kill HIV-infected cells.

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-g secretion with the cytotoxic capacity of freshly-isolated HIV-specific CD8+ T cells.

RESULTS: In a total of 53 different HIV-specific CD8+ T cell populations from 9 different study subjects, we found considerable intraindividual and interindividual differences between cytotoxic- and IFN-g-secreting responses to individuals epitopes, indicating that the execution of these effector functions is only weakly correlated (R=0.51, p=0.002). A substantially stronger relationship (R=0.68, 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-a and interferon-g following viral stimulation. In addition, the subset of interferon-g and TNF-a producing CD8+ T cells exerted stronger cytotoxic effects than the subsets of CD8+ T cells secreting interferon-g only after sorting of these subpopulations according to their cytokine profile. 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-g and TNF-a in response to viral stimulation.

Keywords: AEGIS, HIV-1, Antigens, CD8, T-Lymphocytes, Interferons, Tumor Necrosis Factor-alpha, CD8-Positive T-Lymphocytes, HIV, Acquired Immunodeficiency Syndrome, Interferon Alfa-2b, HIV Infections, Interferon Type II, HIV Seropositivity, Cytokines, HIV Core Protein p24, Anti-HIV Agents, virology, immunology

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MoOrA1051