Towers Greg J, Hatziioannou Theodora, Cowan Simone, Goff Stephen P, Luban Jeremy, Bieniasz Paul D
Department of Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Nat Med. 2003 Sep;9(9):1138-43. doi: 10.1038/nm910. Epub 2003 Aug 3.
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.
许多哺乳动物物种表达限制因子，这些因子赋予宿主对逆转录病毒感染的抗性。我们在此表明，HIV-1对限制因子的敏感性受亲环素A（CypA）调节，CypA是一种与HIV-1衣壳蛋白（CA）结合的宿主细胞蛋白。在某些非人类灵长类动物细胞中，CA-CypA相互作用对于限制至关重要：环孢菌素A（CsA）（该相互作用的竞争性抑制剂）或破坏CypA结合的HIV-1 CA突变可使HIV-1感染性增加100倍以上。相反，人类细胞中CA-CypA相互作用的破坏表明，CypA可保护HIV-1免受Ref-1限制因子的影响。这些发现表明，HIV-1利用了一种宿主细胞蛋白来对抗人类细胞表达的限制因子，并且这种适应性可导致在非天然宿主中对限制敏感。通过限制因子操纵HIV-1 CA识别有望推动HIV-1和艾滋病动物模型及新治疗策略的发展。
