Hollenbaugh Joseph A, Schader Susan M, Schinazi Raymond F, Kim Baek
Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA.
Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA; Veterans Affairs Medical Center, Atlanta, GA, USA.
Virology. 2015 Nov;485:313-21. doi: 10.1016/j.virol.2015.08.006. Epub 2015 Aug 29.
Vpx encoded by HIV-2 and SIVsm enhances retroviral reverse transcription in macrophages in vitro by mediating the degradation of the host SAMHD1 protein that hydrolyzes dNTPs and by elevating cellular dNTP levels. Here we employed RT-SHIV constructs (SIV encoding HIV-1 RT) to investigate the contribution of Vpx to the potency of NRTIs, which compete against dNTPs, in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells. Relative to HIV-1, both SIV and RT-SHIV exhibited reduced sensitivities to AZT, 3TC and TDF in MDMs but not in activated CD4(+) T cells. However, when SIV and RT-SHIV constructs not coding for Vpx were utilized, we observed greater sensitivities to all NRTIs tested using activated CD4(+) T cells relative to the Vpx-coding counterparts. This latter phenomenon was observed for AZT only when using MDMs. Our data suggest that Vpx in RT-SHIVs may underestimate the antiviral efficacy of NRTIs in a cell type dependent manner.
由HIV-2和SIVsm编码的Vpx通过介导宿主SAMHD1蛋白（其水解dNTP）的降解并提高细胞dNTP水平，在体外增强巨噬细胞中的逆转录病毒逆转录。在这里，我们使用RT-SHIV构建体（编码HIV-1 RT的SIV）来研究Vpx对NRTIs（与dNTP竞争）在单核细胞衍生的巨噬细胞（MDM）和活化的CD4(+) T细胞中的效力的贡献。相对于HIV-1，SIV和RT-SHIV在MDM中对AZT、3TC和TDF的敏感性均降低，但在活化的CD4(+) T细胞中未降低。然而，当使用不编码Vpx的SIV和RT-SHIV构建体时，相对于编码Vpx的对应物，我们观察到使用活化的CD4(+) T细胞对所有测试的NRTIs具有更高的敏感性。仅在使用MDM时，AZT才出现后一种现象。我们的数据表明，RT-SHIV中的Vpx可能以细胞类型依赖的方式低估NRTIs的抗病毒功效。
