African Green Monkey TRIM5 alpha Restriction in Simian Immunodeficiency Virus-Specific Rhesus Macaque Effector CD4 T Cells Enhances Their Survival and Antiviral Function

作者：Jain Sumiti; Trivett Matthew T; Ayala Victor I; Ohlen Claes; Ott David E^*

来源：Journal of Virology, 2015, 89(8): 4449-4456.

DOI：10.1128/JVI.03598-14

The expression of xenogeneic TRIM5 alpha proteins can restrict infection in various retrovirus/host cell pairings. Previously, we have shown that African green monkey TRIM5 alpha (AgmTRIM5 alpha) potently restricts both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus mac239 (SIVmac239) replication in a transformed human T-cell line (L. V. Coren, et al., Retrovirology 12:11, 2015, http://dx.doi.org/10.1186/s12977-015-0137-9). To assess AgmTRIM5 alpha restriction in primary cells, we transduced AgmTRIM5 alpha into primary rhesus macaque CD4 T cells and infected them with SIVmac239. Experiments with T-cell clones revealed that AgmTRIM5 alpha could reproducibly restrict SIVmac239 replication, and that this restriction synergizes with an intrinsic resistance to infection present in some CD4 T-cell clones. AgmTRIM5 alpha transduction of virus-specific CD4 T-cell clones increased and prolonged their ability to suppress SIV spread in CD4 target cells. This increased antiviral function was strongly linked to decreased viral replication in the AgmTRIM5 alpha-expressing effectors, consistent with restriction preventing the virus-induced cytopathogenicity that disables effector function. Taken together, our data show that AgmTRIM5 alpha restriction, although not absolute, reduces SIV replication in primary rhesus CD4 T cells which, in turn, increases their antiviral function. These results support prior in vivo data indicating that the contribution of virus-specific CD4 T-cell effectors to viral control is limited due to infection.
IMPORTANCE
The potential of effector CD4 T cells to immunologically modulate SIV/HIV infection likely is limited by their susceptibility to infection and subsequent inactivation or elimination. Here, we show that AgmTRIM5 alpha expression inhibits SIV spread in primary effector CD4 T cells in vitro. Importantly, protection of effector CD4 T cells by AgmTRIM5 alpha markedly enhanced their antiviral function by delaying SIV infection, thereby extending their viability despite the presence of virus. Our in vitro data support prior in vivo HIV-1 studies suggesting that the antiviral CD4 effector response is impaired due to infection and subsequent cytopathogenicity. The ability of AgmTRIM5 alpha expression to restrict SIV infection in primary rhesus effector CD4 T cells now opens an opportunity to use the SIV/rhesus macaque model to further elucidate the potential and scope of anti-AIDS virus effector CD4 T-cell function.

• 出版日期2015-4