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The intestinal tract is a lymphocyte-rich site that undergoes severe depletion of memory CD4+ T cells within days of simian immunodeficiency virus or human immunodeficiency virus type 1 (HIV-1) infection. An ensuing influx of virus-specific CD8+ T cells, which persist throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells or their relationship to the disease course. In this study, we measured CD8+ T-cell responses to HIV-1 peptides in paired rectal and blood samples from chronically infected patients. In both blood and rectum, there was an immunodominant CD8+ T-cell response to HIV Gag compared to Pol and Env (P < 0.01). In contrast, cytomegalovirus pp65 peptides elicited gamma interferon (IFN-γ) secretion strongly in peripheral blood mononuclear cells (PBMC) but weakly in rectal CD8+ T cells (P = 0.015). Upon stimulation with HIV peptides, CD8+ T cells from both sites were capable of mounting complex responses including degranulation (CD107 expression) and IFN-γ and tumor necrosis factor alpha (TNF-γ) production. In rectal tissue, CD107 release was frequently coupled with production of IFN-γ or TNF-α. In patients not on antiretroviral therapy, the magnitude of Gag-specific responses, as a percentage of CD8+ T cells, was greater in the rectal mucosa than in PBMC (P = 0.054); however, the breakdown of responding cells into specific functional categories was similar in both sites. These findings demonstrate that rectal CD8+ T cells are capable of robust and varied HIV-1-specific responses and therefore likely play an active role in eliminating infected cells during chronic infection. [ABSTRACT FROM AUTHOR]