African nonhuman primates that are natural hosts of simian immunodeficiency virus (SIV) are generally spared from disease progression. Pathogenic and nonpathogenic SIV infections share some major features: high viral replication, massive acute depletion of mucosal CD4⁺ T cells, and partial control of the virus by both adaptive and innate immune responses. A key distinction of natural SIV infections is rapid and active control of immune activation and apoptosis of T cells that contributes to the integrity of mucosal barrier and lack of microbial translocation. This allows partial recovery of CD4⁺ T cells and preservation of the function of other immune cell subsets. A better understanding of the mechanisms underlying the lack of disease in natural hosts for SIV infection will likely provide important clues as to the therapy of HIV-1 infection.