Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in old world monkey cells
Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in old world monkey cells
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DOI：
10.1073/pnas.0505659102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Luban, J
中科院分区：
文献类型：
--
作者：
Berthoux, L;Sebastian, S;Luban, J
在人类细胞中，肽基脯氨酸异构酶亲环蛋白A （CypA）在HIV-1衣壳（CA）上包含一个暴露的富含脯氨酸的环，并使逆转录复合物对抗病毒活性具有抗性。新世界猫头鹰猴特有的CypA与TRIM5的融合也针对HIV-1 CA，但这种相互作用有效地抑制感染。旧大陆猴对HIV-1感染的类似阻滞可归因于这些物种中TRIMS同源物的A亚型。为了确定旧大陆猴TRIM5 α对HIV-1的限制是否受到CA-CypA相互作用的调节，我们使用RNA干扰来破坏非洲绿猴和恒河猴细胞中的CypA。CypA敲除后HIV-1的传染性增加，其程度与TRIMS敲除后的增加程度相同。CypA敲除消除了环孢素A（一种CypA-CA相互作用的竞争性抑制剂）或阻断与CypA结合的CA突变体对HIV-1的刺激作用，但不引起与CypA相互作用的逆转录病毒滴度的变化。同时敲除CypA和TRIM5导致滴度的额外增加很小，这表明CypA抑制HIV-1在这些细胞中的复制，因为它是TRIM5 α识别CA所必需的。最后，CsA增加了其他非限制性猫细胞中的HIV-1滴度，但仅在这些细胞被旧大陆猴TRIM5 α转导后。因此，CypA是旧大陆猴TRIM5 α同源基因限制HIV-1所必需的。
The peptidyl-prolyl isomerase cyclophilin A (CypA) embraces an exposed, proline-rich loop on HIV-1 capsid (CA) and renders reverse transcription complexes resistant to an antiviral activity in human cells. A CypA fusion with TRIM5 that is unique to New World owl monkeys also targets HIV-1 CA, but this interaction potently inhibits infection. A similar block to HIV-1 infection in Old World monkeys is attributable to the a isoform of the TRIMS orthologue in these species. To determine whether HIV-1 restriction by Old World monkey TRIM5 alpha is modulated by the CA-CypA interaction, RNA interference was used to disrupt CypA in cells from African green monkeys and rhesus macaques. HIV-1 infectivity increased in response to CypA knock-down to the same extent that it increased in response to TRIMS knock-down. CypA knock-down eliminated the HIV-1 stimulatory effect of cyclosporin A (CsA), a competitive inhibitor of the CypA-CA interaction, or of CA mutants that block binding to CypA but caused no change in titer of retroviruses that don't interact with CypA. Simultaneous knock-down of both CypA and TRIM5 caused minimal additional increase in titer, suggesting that CypA inhibits HIV-1 replication in these cells because it is required for CA recognition by TRIM5 alpha. Finally, CsA increased HIV-1 titer in otherwise nonrestrictive feline cells but only after these cells were transduced with Old World monkey TRIM5 alpha. Thus, CypA is required for HIV-1 restriction by Old World monkey orthologues of TRIM5 alpha.