Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8+ T Cell Killing

Abstract

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, SIV-specific 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.

Importance: Myeloid cells are permissive for HIV/SIV replication in vitro and may contribute to viral persistence in vivo. While many studies have been geared to understanding how CD8(+) T cells control viral replication in CD4(+) T cells, the role of these cells in controlling viral replication in macrophages is less clear. Primary, unstimulated CD8(+) T cells insignificantly suppress viral replication or eliminate SIV-infected macrophages. Since the viral Nef protein downregulates MHC-I and provides infected cells some degree of protection from CD8(+) T cell-mediated effector functions, we evaluated whether Nef may be contributing to the resistance of macrophages to CD8(+) T cell suppression. Our results suggest that Nef is not involved in protecting infected macrophages from CD8(+) T cell killing and suggest that other mechanisms are involved in macrophage evasion from CD8 surveillance.