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, 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. Macrophages may play an important role in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) pathogenesis. Infection of microglia and perivascular macrophages actively mediates entry of HIV-1 into the central nervous system (CNS), resulting in HIV-associated dementia, encephalitis, cognitive disorder, and peripheral neuropathy (1). Accumulating data suggest that tissue macrophages are an important reservoir of virus. Infection of rhesus macaques with a highly pathogenic hybrid simian-human immunodeficiency virus (SHIV) resulted in the rapid depletion of CD4 ϩ T cells such that macrophages were the principal reservoir that sustained high viral loads in the SHIV-infected animals (2). In another study, rhesus macaques depleted of CD4 ϩ T cells exhibited higher viral loads than nondepleted animals, and in situ staining performed on gut tissue revealed that macrophages were the primary source of viral replication (3). It has also been suggested that the level of monocyte turnover is responsible for disease progression in the macaque model of AIDS (4).Macrophages present unique obstacles to infection by primate lentiviruses. The nondividing status of terminally differentiated macrophages and low deoxynucleoside triphosphate (dNTP) levels have to be accommodated in order for primate lentiviruses to establish a productive infection (5, 6). Additionally, macrophages are resistant to the cytopathic effects of viral replication in comparison to the sensitivity of activated ...

HIV Infection of Macrophages: Implications for Pathogenesis and Cure

“…Compared to infected CD4 + T cells, HIV-infected macrophages were less susceptible to CD8 + T-cell-mediated cytoxicity, which agreed with previous reports in the SIV model by Dr. Stevenson and Dr. Watkins [20,21]. This resistance is due to differential susceptibility to granzyme B, which is poorly co-expressed with perforin + ex vivo CD8 + T cells, suggesting a potential mechanism for persistence of an HIV reservoir in macrophages.…”

Splenic Damage during SIV Infection

“…Even though SIV-specific cytotoxic T lymphocytes are numerous within the red pulp, 88 they do not efficiently promote macrophage death. 89 In addition to contributing to SIV infection in the spleen, macrophages are immune to the cytopathic effects of HIV/SIV and may represent a source of latent virus. Our data represent a minimum estimate of the contribution of macrophages to SIV infection in the spleen because of the method used to quantitate infected cells, further underlining the importance of macrophages in HIV/SIV infection.…”

Targeting the Latent Reservoir for HIV-1

“…IFNβ mRNA suppresses LTR activity directly and by inducing a dominant-negative CCAAT/enhancer-binding protein-β (C/EBP-β) that suppresses histone acetylation at the SIV LTR (Barber et al 2006). Low susceptibility of macrophages to CD8 + T cell killing due to decreased granzyme B sensitivity is another proposed mechanism for HIV-1 and SIV persistence (Vojnov et al 2012; Rainho et al 2015; Clayton et al 2017). Interestingly, retroviral infection of these non-dividing cell types is unexpected.…”