Sooty mangabeys are the natural host of simian immunodeficiency virus (SIVsm). When injected into rhesus macaques, SIVsm infection results in progressive declines in CD4(+) T cells, opportunistic infections, and AIDS. In contrast, SIV-infected sooty mangabeys do not develop disease and live an apparently normal life span in captivity, despite maintaining high levels of virus in plasma throughout their lives. Determining the mechanisms by which sooty mangabeys have evolved to resist disease progression and AIDS may be useful in designing effective vaccine and therapeutic strategies to combat HIV-1 infection in humans. This article demonstrates that SIV-infected sooty mangabeys have significantly reduced CCR5 expression on their CD4(+) T cells compared with uninfected mangabeys or rhesus macaques. In contrast, no differences in CCR5 coexpression are found on CD8(+) T cells. Moreover, no differences in absolute numbers of CD4(+) T cells or rates of CD4(+) T cell proliferation were detected between SIV-infected and uninfected mangabeys. Combined, this suggests that either CD4(+) T cells downregulate CCR5 expression, or that CCR5(+)CD4(+) T cells are lost and not replenished in early SIV infection of sooty mangabeys. Regardless of the mechanism involved, significantly lower levels of CCR5 expression on CD4(+) T cells of SIV-infected mangabeys may play a major role in the diminished immune responses and the lack of disease progression in this natural host species.