Nef is dispensable for resistance of simian immunodeficiency virus-infected macrophages to CD8⁺ T cell killing

Simian immunodeficiency virus (SIV)-specific CD8⁺ T cells kill SIV-infected CD4⁺ T cells in an major histocompatibility complex class I (MHC-I)-dependent manner. However, they are reportedly less efficient at killing SIV-infected macrophages. Since the viral accessory protein Nef has been shown to downregulate MHC-I molecules and enhance cytotoxic T lymphocyte (CTL) evasion in human immunodeficiency virus type 1 (HIV-1)-infected CD4⁺ T cells, we examined whether Nef played a role in protecting SIV-infected macrophages from killing by SIV-specific CD8⁺ T cells. To explore the role of Nef in CD8⁺ T cell evasion, we compared the ability of freshly sorted SIV-specific CD8⁺ T cells to readily suppress viral replication or eliminate CD4⁺ T cells or monocyte-derived macrophages infected with SIV variants containing wild-type (WT) or mutated nef genes. As expected, SIVspecific CD8⁺ T cells suppressed viral replication and eliminated the majority of SIV-infected CD4⁺ T cells, and this killing was enhanced in CD4⁺ T cells infected with the nef variants. However, macrophages infected with nef variants that disrupt MHC-I downregulation did not promote rapid killing by freshly isolated CD8⁺ T cells. These results suggest that mechanisms other than Nef-mediated MHC-I downregulation govern the resistance of SIV-infected macrophages to CD8⁺ T cell-mediated killing. This study has implications for viral persistence and suggests that macrophages may afford primate lentiviruses some degree of protection from immune surveillance.