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, 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.


OBJECTIVE
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.
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Jennifer N
JN
Rainho
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Mauricio A
MA
Martins
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Francesc
F
Cunyat
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Ian T
IT
Watkins
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.
David I
DI
Watkins
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA mstevenson@med.miami.edu.
Mario
M
Stevenson
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D003602:Cytotoxicity, Immunologic; D005260:Female; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D057131:Immune Evasion; D016130:Immunophenotyping; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication
D015395:Histocompatibility Antigens Class I; C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins