This review examines simian immunodeficiency virus (SIV) pathogenesis, focusing on SIVmac/smm strains widely used as animal models for AIDS research. SIV naturally infects African primates without causing disease despite high viral replication, but causes severe immunodeficiency when transmitted to new host species like macaques. The virus rapidly disseminates following mucosal or intravenous exposure, initially targeting intraepithelial lymphocytes in gut-associated lymphoid tissue before spreading systemically. Pathogenic infection is characterized by progressive CD4+ T cell depletion, though mechanisms remain incompletely understood. Contributing factors include activation-induced apoptosis in bystander cells, viral accessory genes (particularly nef, vpx, and vpr), and altered lymphocyte distribution. SIV also causes enteropathy and neuropathology, with virus entry into the brain occurring early in infection through mechanisms still being elucidated. The Nef protein plays a critical role in pathogenesis through multiple functions including downregulation of CD4 from cell surfaces and interaction with T cell signaling machinery. Host factors influencing disease include species differences, age, and immune responses. Understanding these pathogenic mechanisms in the SIV model provides insights into HIV-related disease processes in humans.

Key findings

• SIV causes apathogenic infections in natural hosts (African green monkeys, sooty mangabeys) but induces severe immunodeficiency when transmitted to new host species like macaques, with disease severity correlating to viral replication levels
• Rapid viral dissemination following mucosal or intravenous exposure targets gut-associated lymphoid tissue CD4+ T cells within days, preceding peripheral immune changes; intraepithelial lymphocytes are primary early infection targets
• The Nef accessory protein is essential for pathogenesis, controlling CD4 downregulation, T cell activation, FasL expression, and apoptosis induction; nef-deleted mutants remain disease-free with greatly reduced viral loads
• Viral coreceptor usage involves CCR5 and additional chemokine receptors (Bonzo, BOB), with some SIV strains capable of CD4-independent brain endothelial cell infection via CCR5-mediated mechanisms
• Host immune responses, particularly cytotoxic T lymphocyte activity and pre-existing immunity from vaccination, can significantly reduce disease progression and viral loads, though protective mechanisms remain incompletely understood