Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5.
Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5.
复制标题
在缺乏 SERINC3 和 SERINC5 的情况下，Nef 有效增强 HIV-1 复制。
DOI：
10.1128/mbio.01071-19
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发表时间：
2019
期刊：
影响因子：
6.4
通讯作者：
Göttlinger,Heinrich
中科院分区：
文献类型：
--
作者：
Wu,Yuanfei;Olety,Balaji;Weiss,EricR;Popova,Elena;Yamanaka,Hikaru;Göttlinger,Heinrich
最近发现HIV-1 Nef对抗抗病毒宿主蛋白SERINC 3和SERINC 5。特别地，SERINC 5在掺入时抑制子代病毒体的感染性。SERINC 3和SERINC 5也被不相关的鼠白血病病毒糖基化Gag（glycoGag）蛋白抵消，该蛋白对HIV-1感染性具有有效的Nef样活性。我们现在报告称，一个最小的glycoGag称为glycoMA可以完全取代Nef在促进HIV-1复制在Jurkat T淋巴细胞，表明Nef增强复制在这些细胞主要是通过抵消丝氨酸蛋白酶抑制剂。相比之下，SERINC拮抗剂glycoMA不能替代MOLT-3 T淋巴细胞中的Nef，其中HIV-1复制高度依赖于Nef，并且即使在没有SERINC 3和SERINC 5的情况下也保持如此。在MOLT-3细胞中，glycoMA不能替代Nef刺激HIV-1在原代人细胞中的复制。虽然Nef突变体促进HIV-1在MOLT-3细胞中复制的能力与参与内吞机制和下调CD 4的能力相关，但Nef在CD 4下调未发生的条件下挽救了病毒复制。两者合计，我们的观察提高了Nef触发一种新的抗病毒因子的内吞作用的可能性，该因子对实验室适应和主要HIV-1 strain.IMPORTANCEThe Nef蛋白的HIV-1和无关的glycoGag蛋白的小鼠白血病病毒类似地防止被称为SERINC 3和SERINC 5的抗病毒宿主蛋白的摄取到HIV-1颗粒中，这增强了它们的感染性。我们现在表明，虽然这两种SERINC拮抗剂原则上可以类似地增强HIV-1复制，但glycoGag无法在原代人类细胞和称为MOLT-3的T细胞系中取代Nef。在MOLT-3细胞中，Nef对HIV-1复制仍然至关重要，即使在没有SERINC 3和SERINC 5的情况下。Nef对HIV-1在MOLT-3细胞中传播的显著作用与Nef参与细胞内吞机制和下调HIV-1受体CD 4的能力相关，但在没有CD 4下调的情况下仍然存在。总的来说，我们的研究结果提供了一个强大的新的限制活性，甚至影响相对SERINC耐药的HIV-1分离株，并抵消Nef的证据。
It has recently emerged that HIV-1 Nef counteracts the antiviral host proteins SERINC3 and SERINC5. In particular, SERINC5 inhibits the infectivity of progeny virions when incorporated. SERINC3 and SERINC5 are also counteracted by the unrelated murine leukemia virus glycosylated Gag (glycoGag) protein, which possesses a potent Nef-like activity on HIV-1 infectivity. We now report that a minimal glycoGag termed glycoMA can fully substitute for Nef in promoting HIV-1 replication in Jurkat T lymphoid cells, indicating that Nef enhances replication in these cells mainly by counteracting SERINCs. In contrast, the SERINC antagonist glycoMA was unable to substitute for Nef in MOLT-3 T lymphoid cells, in which HIV-1 replication was highly dependent on Nef, and remained so even in the absence of SERINC3 and SERINC5. As in MOLT-3 cells, glycoMA was unable to substitute for Nef in stimulating HIV-1 replication in primary human cells. Although the ability of Nef mutants to promote HIV-1 replication in MOLT-3 cells correlated with the ability to engage endocytic machinery and to downregulate CD4, Nef nevertheless rescued virus replication under conditions where CD4 downregulation did not occur. Taken together, our observations raise the possibility that Nef triggers the endocytosis of a novel antiviral factor that is active against both laboratory-adapted and primary HIV-1 strains.IMPORTANCEThe Nef protein of HIV-1 and the unrelated glycoGag protein of a murine leukemia virus similarly prevent the uptake of antiviral host proteins called SERINC3 and SERINC5 into HIV-1 particles, which enhances their infectiousness. We now show that although both SERINC antagonists can in principle similarly enhance HIV-1 replication, glycoGag is unable to substitute for Nef in primary human cells and in a T cell line called MOLT-3. In MOLT-3 cells, Nef remained crucial for HIV-1 replication even in the absence of SERINC3 and SERINC5. The pronounced effect of Nef on HIV-1 spreading in MOLT-3 cells correlated with the ability of Nef to engage cellular endocytic machinery and to downregulate the HIV-1 receptor CD4 but nevertheless persisted in the absence of CD4 downregulation. Collectively, our results provide evidence for a potent novel restriction activity that affects even relatively SERINC-resistant HIV-1 isolates and is counteracted by Nef.