Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors
Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors
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DOI：
10.1038/nm910
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发表时间：
2003-09-01
期刊：
影响因子：
82.9
通讯作者：
Bieniasz, PD
中科院分区：
文献类型：
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作者：
Towers, GJ;Hatziioannou, T;Bieniasz, PD
许多哺乳动物物种表达限制因子，赋予宿主对逆转录病毒感染的抗性。在这里，我们表明，HIV-1的限制性因子的敏感性是由亲环素A（CypA），结合HIV-1衣壳蛋白（CA）的宿主细胞蛋白调制。在某些非人类灵长类细胞中，CA-CypA相互作用对于限制是必不可少的：HIV-1感染性通过环孢菌素A（CsA）（相互作用的竞争性抑制剂）或通过破坏CypA结合的HIV-1 CA突变增加>100倍。相反，在人类细胞中CA-CypA相互作用的破坏表明CypA保护HIV-1免受Ref-1限制因子的影响。这些发现表明，HIV-1已经选择了一种宿主细胞蛋白来抵消人类细胞表达的限制因子，这种适应可以赋予非天然宿主对限制的敏感性。通过限制因子操纵HIV-1 CA识别有望推进HIV-1和AIDS的动物模型和新的治疗策略。
Many mammalian species express restriction factors that confer host resistance to retroviral infection. Here we show that HIV-1 sensitivity to restriction factors is modulated by cyclophilin A (CypA), a host cell protein that binds the HIV-1 capsid protein (CA). In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding. Conversely, disruption of CA-CypA interaction in human cells reveals that CypA protects HIV-1 from the Ref-1 restriction factor. These findings suggest that HIV-1 has co-opted a host cell protein to counteract restriction factors expressed by human cells and that this adaptation can confer sensitivity to restriction in unnatural hosts. Manipulation of HIV-1 CA recognition by restriction factors promises to advance animal models and new therapeutic strategies for HIV-1 and AIDS.