Cytotoxic granule release dominates gag-specific CD4+ T-cell response in different phases of HIV infection

BACKGROUND: The activity of virus-specific T lymphocytes, among which those capable of a polyfunctional response against the viral protein gag, is crucial to control HIV infection. OBJECTIVE: The objective of this study is to investigate the polyfunctionality of gag-specific T cells in different phases of HIV infection, analyzing markers related to T-helper cell 1 (Th1) and degranulation/cytotoxicity, and the production of Th1 cytokines in peripheral blood lymphocytes from patients experiencing an acute primary infection, long-term nonprogressors, patients naive for antiretroviral drugs, and patients taking HAART. MATERIALS AND METHODS: Cells were stimulated with a pool of gag-derived peptides or with a superantigen (staphylococcal enterotoxin B). Using eight-color polychromatic flow cytometry, we analyzed the expression of interleukin-2, interferon-γ, CD154⁺, and CD107a by CD4 ⁺ and CD8⁺ T cells. RESULTS: The main finding was that in all HIV-positive patients, about half gag-specific CD4 T cells were CD107a, that is, able to degranulate. CD4⁺CD154⁺ cells unable to produce Th1 cytokines were the second most represented population. Truly polyfunctional CD4⁺ T cells were very rare and present only in a few long-term nonprogressors. Superantigen stimulation showed that CD4⁺T lymphocytes from all patients displayed a typical Th response, including interleukin-2 and interferon-γ production, lacking CD107a expression. CONCLUSION: In all the aforementioned phases of HIV infection, the large majority of gag-specific CD4⁺ T lymphocytes cannot be identified by the sole expression of interleukin-2 and interferon-γ, which is early impaired. Degranulation and helper functions other than Th1 cytokine production are the predominant features of HIV-specific CD4⁺ lymphocytes.