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To evaluate HIV-2-specific proliferative, interferon (IFN)γ- and interleukin (IL)-2-producing T-cell responses in HIV-2 infection and their relationship with plasma HIV-2 RNA.HIV-2-Gag-p26 and cytomegalovirus (CMV)-specific CD4 T-cell responses from 19 untreated HIV-2-infected subjects (median CD4 cell counts, 561 × 106/l) were compared by lymphoproliferation assay, IFNγ secretion in culture supernatants by ELISA, and intracellular staining (ICS) of IFNγ and IL-2. CD8 responses were assessed by IFNγ-ELISpot using pools of SIVmac239-Gag peptides (87% of homology with HIV-2).HIV-2-specific IFNγ production was detected in 53% and 92% patients by ELISA and ICS, respectively, while HIV-2-specific IL-2 production was detected in only 33% by ICS and lymphoproliferation in 21% patients. All IL-2-producing CD4 T cells co-produced IFNγ. Overall, frequencies of Th1 responses to HIV-2 were similar to CMV in subjects with undetectable plasma HIV-2 RNA, while significantly lower than CMV in HIV-2 RNA-positive subjects, despite similar CD4 cell counts in both groups. In addition, proliferative responses to HIV-2 were correlated to IFNγ secretion (r > 0.68, P < 0.01), and were significantly higher in HIV-2 RNA-negative (P < 0.05) than in HIV-2 RNA-positive subjects. Frequencies of SIV-Gag-specific CD8 cells, detected in 93% of patients, were also higher in HIV-2 RNA-negative subjects, though not significantly. Overall, HIV-2-specific T-cell responses were not correlated to CD4 cell counts.Proliferative, IFNγ- and IL-2-producing T-cell responses to HIV-2 are as robust as CMV-specific responses in untreated HIV-2 subjects with undetectable plasma HIV-2 levels, independently of CD4 cell depletion and despite lower frequencies of IL-2-producing T cells compared to IFNγ. In addition, lymphoproliferative responses to HIV-2 were associated with lack of viral replication.