Immunocompromised Host Research Section, Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, PO Box 3354 (MBC-03), Riyadh, 11211, Kingdom of Saudi Arabia.
Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Sci Rep. 2021 Oct 25;11(1):20984. doi: 10.1038/s41598-021-00415-2.
SAMHD1, a human host factor found in myeloid cells which restricts HIV-1 replication. It depletes the dNTPs pool for viral cDNA syntheses, thus preventing the viral replication in the cells. The viral accessory protein, Vpx, exists only in SIVmac/HIV-2 particles. Vpx in SIVmac can induce proteosomal degradation of SAMHD1, which then leads to a decrease in the cytoplasmic dNTP pool. The protein-protein interaction between Vpx and SAMHD1 and its consequences are still unclear. Methods: In this study, we cloned, for the first time, Vpx gene from a HIV-2 infected patient and found up to 30% sequence variation compared to known HIV-2 strains. We then analyzed the role of SAMHD1 protein expression in transfected THP-1 and U937 cells by transfecting with the Vpx gene derived from SIVmac, HIV-2 from the NIH sample as well as HIV-2 from a Saudi patient. We found that Vpx gene expression led to reduced levels of intracellular SAMHD1. When the supernatants of the transfected cell lines were examined for secreted cytokines, chemokines and growth factors, Vpx expression seemed to be suppressive of pro-inflammatory response, and skewed the immune response towards an anti-inflammatory response. These results suggest that Vpx can act at two levels: clearance of intracellular restriction factor and suppression of cytokine storm: both aimed at long-term latency and host-pathogen stand-off, suggesting that Vpx is likely to be a potential therapeutic target.
SAMHD1 是一种存在于髓系细胞中的人类宿主因子，可限制 HIV-1 的复制。它会耗尽病毒 cDNA 合成所需的 dNTP 池，从而阻止细胞中的病毒复制。病毒辅助蛋白 Vpx 仅存在于 SIVmac/HIV-2 颗粒中。SIVmac 中的 Vpx 可诱导 SAMHD1 的蛋白酶体降解，从而导致细胞质 dNTP 池减少。Vpx 与 SAMHD1 之间的蛋白-蛋白相互作用及其后果尚不清楚。方法：在这项研究中，我们首次从一名 HIV-2 感染者中克隆了 Vpx 基因，并发现与已知的 HIV-2 株相比，有多达 30%的序列变异。然后，我们通过转染 SIVmac、NIH 样本中的 HIV-2 以及沙特患者的 HIV-2 的 Vpx 基因，分析了 SAMHD1 蛋白表达在转染的 THP-1 和 U937 细胞中的作用。我们发现 Vpx 基因表达导致细胞内 SAMHD1 水平降低。当检查转染细胞系的上清液中是否有分泌的细胞因子、趋化因子和生长因子时，Vpx 表达似乎抑制了促炎反应，并使免疫反应偏向抗炎反应。这些结果表明，Vpx 可以在两个层面上发挥作用：清除细胞内的限制因子和抑制细胞因子风暴：这两者都旨在实现长期潜伏和宿主-病原体对峙，这表明 Vpx 可能是一个潜在的治疗靶点。
