Identifying distinctions between pathogenic HIV and simian immunodeficiency virus (SIV) infections and nonprogressive SIV in natural African primate hosts might provide key insights into HIV pathogenesis. Similar to pathogenic HIV infection in humans, natural SIV infections result in high viral replication and massive acute depletion of mucosal CD4⁺ T cells. A key distinction of natural SIV infections is a rapidly developing anti-inflammatory milieu that prevents chronic activation, apoptosis and proliferation of T cells and preserves the function of other immune cell subsets, thus contributing to the integrity of the mucosal barrier and the lack of microbial translocation from the gut to the peritoneum. Immunologic features observed during natural SIV infections suggest approaches for designing new strategies for producing novel second-generation vaccines and therapeutic approaches to inhibit disease progression in HIV-infected humans.