SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef.
SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef.
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DOI：
10.1038/nature15400
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发表时间：
2015-10-08
期刊：
影响因子：
64.8
通讯作者：
Göttlinger HG
中科院分区：
文献类型：
--
作者：
Usami Y;Wu Y;Göttlinger HG
HIV-1 Nef和不相关的小鼠白血病病毒糖gag以网格蛋白依赖的方式强烈增强在某些细胞类型中产生的HIV-1病毒粒子的感染性。在这里，我们发现Nef和glycoGag在一定程度上阻止了多通跨膜蛋白SERINC3和SERINC5与HIV-1病毒粒子的结合，这与传染性增强有关。SERINC3和SERINC5的沉默精确地反映了Nef和glycoGag对HIV-1感染的影响。在缺乏SERINC3和SERINC5的双敲除人CD4+ T细胞中产生的nef缺陷病毒粒子的传染性增加了100倍以上，重新表达实验证实，缺乏SERINC3和SERINC5是传染性增强的原因。此外，SERINC3和SERINC5共同限制了HIV-1的复制，而Nef规避了这种限制。SERINC3和SERINC5在人类HIV-1原代靶细胞中高度表达，通过Nef抑制其下调是对抗HIV/AIDS的潜在策略。
HIV-1 Nef and the unrelated murine leukemia virus glycoGag strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Here we show that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins SERINC3 and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of SERINC3 together with SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivities. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4+ T cells that lack both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS.