Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization
Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization
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DOI：
10.1128/jvi.01406-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Whitby, Kevin
中科院分区：
文献类型：
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作者：
Shi, Jiong;Zhou, Jing;Whitby, Kevin
人类免疫缺陷病毒1型（HIV-1）感染依赖于病毒衣壳在靶细胞中的正确分解或“脱壳”。HIV-1衣壳由病毒衣壳蛋白（CA）的锥形多聚体复合物组成，以六边形晶格排列。由于靶细胞逆转录缺陷，CA中使病毒衣壳不稳定的突变会导致感染受损。我们在这里描述了一种小分子HIV-1抑制剂PF-3450074（PF 74）的作用机制，它靶向CA。PF 74在HIV-1感染的早期阶段起作用，并抑制靶细胞中的逆转录。我们表明，PF 74特异性结合HIV-1颗粒，并在CA中的取代，赋予耐药性的化合物防止结合。CA中稳定HIV-1核心的单点突变也赋予了对病毒的强抗性，而不抑制化合物结合。用PF 74处理HIV-1颗粒或纯化的核心在体外使病毒衣壳不稳定。此外，该化合物诱导HIV-1衣壳在靶细胞中快速溶解。PF 74的抗病毒活性是通过将宿主蛋白亲环素A结合到HIV-1衣壳上来促进的，并且PF 74和环孢素表现出相互拮抗作用。我们的数据表明，PF 74触发过早的HIV-1在靶细胞中脱壳，从而模拟逆转录病毒限制因子TRIM 5 α的活性。这项研究强调了脱壳作为HIV-1生命周期中易受小分子干预的一个步骤。
Human immunodeficiency virus type 1 (HIV-1) infection is dependent on the proper disassembly of the viral capsid, or "uncoating," in target cells. The HIV-1 capsid consists of a conical multimeric complex of the viral capsid protein (CA) arranged in a hexagonal lattice. Mutations in CA that destabilize the viral capsid result in impaired infection owing to defects in reverse transcription in target cells. We describe here the mechanism of action of a small molecule HIV-1 inhibitor, PF-3450074 (PF74), which targets CA. PF74 acts at an early stage of HIV-1 infection and inhibits reverse transcription in target cells. We show that PF74 binds specifically to HIV-1 particles, and substitutions in CA that confer resistance to the compound prevent binding. A single point mutation in CA that stabilizes the HIV-1 core also conferred strong resistance to the virus without inhibiting compound binding. Treatment of HIV-1 particles or purified cores with PF74 destabilized the viral capsid in vitro. Furthermore, the compound induced the rapid dissolution of the HIV-1 capsid in target cells. PF74 antiviral activity was promoted by binding of the host protein cyclophilin A to the HIV-1 capsid, and PF74 and cyclosporine exhibited mutual antagonism. Our data suggest that PF74 triggers premature HIV-1 uncoating in target cells, thereby mimicking the activity of the retrovirus restriction factor TRIM5 alpha. This study highlights uncoating as a step in the HIV-1 life cycle that is susceptible to small molecule intervention.