Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
Retrovirology. 2011 Jun 22;8:49. doi: 10.1186/1742-4690-8-49.
Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys). HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta), also encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. This activity correlates with Vpx binding to DCAF1 (VPRBP) and association with the DDB1/RBX1/CUL4A E3 ubiquitin ligase complex. When delivered experimentally to myeloid cells using VSV G-pseudotyped virus-like particles (VLPs), Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx.
Here we show that Vpx has the extraordinary ability to completely rescue HIV-1 transduction of human monocyte-derived dendritic cells (MDDCs) from the potent antiviral state established by prior treatment with exogenous type 1 interferon (IFN). The magnitude of rescue was up to 1,000-fold, depending on the blood donor, and was also observed after induction of endogenous IFN and IFN-stimulated genes (ISGs) by LPS, poly(I:C), or poly(dA:dT). The effect was relatively specific in that Vpx-associated suppression of soluble IFN-β production, of mRNA levels for ISGs, or of cell surface markers for MDDC differentiation, was not detected. Vpx did not rescue HIV-2 or SIVMAC transduction from the antiviral state, even in the presence of SIVMAC or HIV-2 VLPs bearing additional Vpx, or in the presence of HIV-1 VLPs bearing all accessory genes. In contrast to the effect of Vpx on transduction of untreated MDDCs, HIV-1 rescue from the antiviral state was not dependent upon Vpx interaction with DCAF1 or on the presence of DCAF1 within the MDDC target cells. Additionally, although Vpx increased the level of HIV-1 reverse transcripts in MDDCs to the same extent whether or not MDDCs were treated with IFN or LPS, Vpx rescued a block specific to the antiviral state that occurred after HIV-1 cDNA penetrated the nucleus.
Vpx provides a tool for the characterization of a potent, new HIV-1 restriction activity, which acts in the nucleus of type 1 IFN-treated dendritic cells.
Vpx 是一种由 SIVSM 编码的病毒相关蛋白，SIVSM 是一种内源性慢病毒，存在于西非黑长尾猴（Cercocebus atys）中。HIV-2 和 SIVMAC 是由 SIVSM 传播给人类或亚洲恒河猴（Macaca mulatta）而产生的人畜共患病，它们也编码 Vpx。在髓系细胞中，Vpx 促进这些病毒的逆转录和转导。这种活性与 Vpx 与 DCAF1（VPRBP）结合和与 DDB1/RBX1/CUL4A E3 泛素连接酶复合物相关联。当使用 VSV G 假型病毒样颗粒（VLPs）实验性递送到髓系细胞时，Vpx 促进了不通常编码 Vpx 的逆转录病毒的逆转录。
在这里，我们表明 Vpx 具有非凡的能力，可以完全挽救人类单核细胞衍生的树突状细胞（MDDC）中 HIV-1 的转导，从而逆转由外源性 1 型干扰素（IFN）预先处理建立的强大抗病毒状态。挽救的幅度高达 1000 倍，这取决于供体，并且在用 LPS、多聚（I：C）或多聚（dA：dT）诱导内源性 IFN 和 IFN 刺激基因（ISGs）后也观察到。这种作用相对特异性，因为没有检测到 Vpx 相关的可溶性 IFN-β产生、ISGs 的 mRNA 水平或 MDDC 分化的细胞表面标记物的抑制。Vpx 不能从抗病毒状态中挽救 HIV-2 或 SIVMAC 的转导，即使存在带有额外 Vpx 的 SIVMAC 或 HIV-2 VLPs，或存在带有所有辅助基因的 HIV-1 VLPs 也是如此。与 Vpx 对未处理的 MDDC 转导的影响相反，从抗病毒状态中拯救 HIV-1 不依赖于 Vpx 与 DCAF1 的相互作用，也不依赖于 DCAF1 是否存在于 MDDC 靶细胞中。此外，尽管 Vpx 使 MDDC 中的 HIV-1 逆转录本水平增加到相同程度，无论 MDDC 是否用 IFN 或 LPS 处理，但 Vpx 挽救了发生在 HIV-1 cDNA 穿透核后针对抗病毒状态的特异性阻断。
Vpx 为表征一种新的强效 HIV-1 限制活性提供了一种工具，该活性作用于 1 型 IFN 处理的树突状细胞的核内。
Zotero 插件
