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To demonstrate that, despite a dose-dependent cytostatic effect, hydroxyurea (HU) does not have immunosuppressive effects.The effects of HU on T lymphocyte proliferation parameters, activation phenotype and cytokine production were examined in vitro after exposure to clinically relevant concentrations of HU (10, 50, and 100 μmol/l). The effects of HU in vivo on CD4 T cell counts, viral load, activation phenotype and virus-specific response were examined in 17 Rhesus macaques infected with SIVmac251 and randomized into three groups: untreated controls; treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and didanosine (ddI) only; and treated with PMPA, didanosine, and HU.The in vitro inhibition of T lymphocyte proliferation confirmed the cytostatic effect of HU, with a linear dose-dependent effect; however, no relevant differences were found in the expression of activation markers between treated and untreated controls. Both T helper type 1 and type 2 cytokine production were enhanced by HU. Consistent with the in vitro results, a blunted increase of peripheral CD4 T cells was observed in vivo in the HU group, without relevant effects on the expression of activation markers, and SIV-specific T cell responses were not affected by HU.Hyper-proliferation of T-lymphocytes is a major factor contributing to HIV pathogenesis. HU exerts a cytostatic effect on T lymphocytes, without altering their activation and apparently without having an immunosuppressive effect. The increase in cytokine production at the single cell level might compensate for the decrease in the percentage of activated CD4 T lymphocytes, without overall impairment of HIV-specific immune responses.