Jain Sumiti, Trivett Matthew T, Ayala Victor I, Ohlen Claes, Ott David E
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
J Virol. 2015 Apr;89(8):4449-56. doi: 10.1128/JVI.03598-14. Epub 2015 Feb 4.
The expression of xenogeneic TRIM5α proteins can restrict infection in various retrovirus/host cell pairings. Previously, we have shown that African green monkey TRIM5α (AgmTRIM5α) potently restricts both human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus mac239 (SIV(mac239)) 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 AgmTRIM5α restriction in primary cells, we transduced AgmTRIM5α into primary rhesus macaque CD4 T cells and infected them with SIV(mac239). Experiments with T-cell clones revealed that AgmTRIM5α could reproducibly restrict SIV(mac239) replication, and that this restriction synergizes with an intrinsic resistance to infection present in some CD4 T-cell clones. AgmTRIM5α 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 AgmTRIM5α-expressing effectors, consistent with restriction preventing the virus-induced cytopathogenicity that disables effector function. Taken together, our data show that AgmTRIM5α 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.
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 AgmTRIM5α expression inhibits SIV spread in primary effector CD4 T cells in vitro. Importantly, protection of effector CD4 T cells by AgmTRIM5α 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 AgmTRIM5α 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.
异种TRIM5α蛋白的表达可限制多种逆转录病毒/宿主细胞组合中的感染。此前，我们已表明非洲绿猴TRIM5α（AgmTRIM5α）可有效限制1型人类免疫缺陷病毒（HIV-1）和猴免疫缺陷病毒mac239（SIV（mac239））在转化的人T细胞系中的复制（L.V.科伦等人，《逆转录病毒学》12:11，2015年，http://dx.doi.org/10.1186/s12977-015-0137-9）。为评估AgmTRIM5α在原代细胞中的限制作用，我们将AgmTRIM5α转导至原代恒河猴CD4 T细胞中，并用SIV（mac239）感染它们。对T细胞克隆的实验表明，AgmTRIM5α可重复性地限制SIV（mac239）的复制，且这种限制与一些CD4 T细胞克隆中存在的对感染的固有抗性协同作用。病毒特异性CD4 T细胞克隆的AgmTRIM5α转导增强并延长了它们抑制SIV在CD4靶细胞中传播的能力。这种增强的抗病毒功能与在表达AgmTRIM5α的效应细胞中病毒复制的减少密切相关，这与限制作用防止了使效应细胞功能丧失的病毒诱导的细胞致病性一致。综上所述，我们的数据表明，AgmTRIM5α的限制作用虽然不是绝对的，但可减少原代恒河猴CD4 T细胞中的SIV复制，进而增强它们的抗病毒功能。这些结果支持了先前的体内数据，表明病毒特异性CD4 T细胞效应器对病毒控制的贡献因感染而受到限制。
效应性CD4 T细胞在免疫调节SIV/HIV感染方面的潜力可能因其对感染的易感性以及随后的失活或清除而受到限制。在此，我们表明AgmTRIM5α的表达在体外可抑制SIV在原代效应性CD4 T细胞中的传播。重要的是，AgmTRIM5α对效应性CD4 T细胞的保护通过延迟SIV感染显著增强了它们的抗病毒功能，从而在存在病毒的情况下延长了它们的存活能力。我们的体外数据支持了先前关于HIV-1的体内研究，表明抗病毒CD4效应反应因感染和随后的细胞致病性而受损。AgmTRIM5α表达在原代恒河猴效应性CD4 T细胞中限制SIV感染的能力现在为利用SIV/恒河猴模型进一步阐明抗艾滋病病毒效应性CD4 T细胞功能的潜力和范围提供了机会。
