HIV-2 is known to display an attenuated phenotype in vivo with prolonged time to disease and decreased rate of transmission. Observational studies in Senegal have demonstrated protection from HIV-1 infection, although the putative mechanism for immunoprotection remains undefined. We evaluated HIV-2-seropositive women from a cohort of commercial sex workers in Dakar, Senegal and identified individuals with very low surface CCR5 receptor expression on CD4+ T cells. In vitro up-regulation of the CCR5 receptor was readily achieved. Down-regulation of the CCR5 was not correlated with activation markers (HLA-DR), beta-chemokine levels, or plasma viral loads. A correlation was observed with HIV-2-specific CD8+ T cell activity as measured by intracellular cytokine production. We postulate that down-regulation of the CCR5 receptor in HIV-2 infection contributes to slower disease course and to the protective mechanism against HIV-1 superinfection, mediated in part by HIV-2-specific cellular immune responses.