Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4⁺CCR5⁺ T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4⁺ T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4⁺ central memory T cells (T_CM cells). CD4⁺ T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4⁺ T cell depletion. Sooty mangabey CD4⁺ T_CM cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4⁺ T_CM cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4⁺ T cells favors the preservation of CD4⁺ T cell homeostasis and promotes an AIDS-free status by protecting CD4⁺ T_CM cells from direct virus infection.