Molecular mechanisms by which HERV-K Gag interferes with HIV-1 Gag assembly and particle infectivity.
Molecular mechanisms by which HERV-K Gag interferes with HIV-1 Gag assembly and particle infectivity.
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DOI：
10.1186/s12977-017-0351-8
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发表时间：
2017-04-26
期刊：
影响因子：
3.3
通讯作者：
Ono A
中科院分区：
文献类型：
--
作者：
Monde K;Terasawa H;Nakano Y;Soheilian F;Nagashima K;Maeda Y;Ono A
人类内源性逆转录病毒（herv）是古代逆转录病毒感染的残余，约占人类基因组DNA的8%。由于HERV-K Gag在T细胞中是由HIV-1 Tat诱导表达的，因此诱导的HERV-K蛋白可以影响HIV-1的复制。事实上，之前我们发现HERV-K Gag和HIV-1 Gag共同聚集，这似乎与HERV-K Gag表达对HIV-1颗粒释放及其传染性的影响有关。我们进一步表明，共组装需要MA和NC结构域，它们可能通过分别结合膜和RNA的能力作为Gag的支架。然而，值得注意的是，尽管具有这些能力，MLV Gag不能与HIV-1 Gag共同组装，也不影响HIV-1颗粒的组装和感染性。目前尚不清楚共聚集的特异性是如何确定的。在这里，我们发现HERV-K Gag与HIV-1 Gag的共表达改变了后代HIV-1颗粒的大小和形态，并严重降低了这些后代病毒的传染性。我们进一步比较了HERV-K-MLV嵌合结构，以确定共组装特异性和抑制HIV-1释放效率和感染性的分子决定因素。我们发现HERV-K Gag的CA n端结构域（NTD）对降低HIV-1释放效率很重要，而CA-NTD和HERV-K Gag的主要同源区域都有助于与HIV-1 Gag共定位。有趣的是，这些HERV-K Gag区域并不是降低后代HIV-1传染性所必需的。我们的研究结果表明，HERV-K Gag CA对降低HIV-1释放和传染性很重要，但CA内的不同区域参与了对HIV-1释放和传染性的影响。总之，这些发现揭示了HERV-K Gag通过两种不同的分子机制干扰HIV-1的复制。本文的在线版本（doi:10.1186/s12977-017-0351-8）包含补充材料，可供授权用户使用。
Human endogenous retroviruses (HERVs), the remnants of ancient retroviral infections, constitute approximately 8% of human genomic DNA. Since HERV-K Gag expression is induced by HIV-1 Tat in T cells, induced HERV-K proteins could affect HIV-1 replication. Indeed, previously we showed that HERV-K Gag and HIV-1 Gag coassemble and that this appears to correlate with the effect of HERV-K Gag expression on HIV-1 particle release and its infectivity. We further showed that coassembly requires both MA and NC domains, which presumably serve as scaffolding for Gag via their abilities to bind membrane and RNA, respectively. Notably, however, despite possessing these abilities, MLV Gag failed to coassemble with HIV-1 Gag and did not affect assembly and infectivity of HIV-1 particles. It is unclear how the specificity of coassembly is determined. Here, we showed that coexpression of HERV-K Gag with HIV-1 Gag changed size and morphology of progeny HIV-1 particles and severely diminished infectivity of such progeny viruses. We further compared HERV-K-MLV chimeric constructs to identify molecular determinants for coassembly specificity and for inhibition of HIV-1 release efficiency and infectivity. We found that the CA N-terminal domain (NTD) of HERV-K Gag is important for the reduction of the HIV-1 release efficiency, whereas both CA-NTD and major homology region of HERV-K Gag contribute to colocalization with HIV-1 Gag. Interestingly, these regions of HERV-K Gag were not required for reduction of progeny HIV-1 infectivity. Our results showed that HERV-K Gag CA is important for reduction of HIV-1 release and infectivity but the different regions within CA are involved in the effects on the HIV-1 release and infectivity. Altogether, these findings revealed that HERV-K Gag interferes the HIV-1 replication by two distinct molecular mechanisms. The online version of this article (doi:10.1186/s12977-017-0351-8) contains supplementary material, which is available to authorized users.