Antiretroviral Activity of TRIM5alpha

描述（由申请人提供）：在进入宿主细胞后，逆转录病毒可以在某些物种的细胞中被显性宿主因子阻断。例如，人类免疫缺陷病毒（HIV-1），获得性免疫缺陷综合征（艾滋病）的病原体，在大多数旧大陆猴子的细胞中遇到进入后的阻塞。相比之下，相关的猴免疫缺陷病毒（SIV）的感染在新大陆猴子中受到限制。某些小鼠白血病病毒（mlv）进入人类细胞后很快被阻断。所有这些进入后限制都有共同的特点：1)阻滞发生在逆转录之前或早期阶段；2)病毒对酶切易感性的决定因素是衣壳蛋白；3)宿主细胞限制因子可以被含有限制衣壳的病毒样颗粒竞争。限制恒河猴HIV-1的因子已被确定为trim5 α。人类同源物也能抑制HIV-1感染，但不如恒河猴TRIM5alpha有效。在这项应用中，我们提出：1)鉴定灵长类TRIM5alpha蛋白抗病毒效力的决定因素；2)了解trim5 α的种间变异对该蛋白限制特定逆转录病毒能力的影响；3)阐明TRIM5alpha强抗病毒作用的机制。

DESCRIPTION (provided by applicant): Following entry into the host cell, retroviruses can be blocked in the cells of certain species by dominant acting host factors. For example, human immunodeficiency virus (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), encounters a post-entry block in the cells of most Old World monkeys. By contrast, infection by the related simian immunodeficiency virus (SIV) is restricted in New World monkeys. Certain strains of murine leukemia viruses (MLVs) enter human cells but are blocked soon thereafter. All of these post-entry restrictions share common features: 1) the block occurs prior to or at the early stage of reverse transcription; 2) the viral determinant of the susceptibility to restriction is the capsid protein; and 3) the host cell restricting factor can be competed by virus-like particles containing the restricted capsid. The factor restricting HIV-1 in rhesus monkeys has been identified as TRIM5alpha. The human orthologue can also inhibit HIV-1 infection, but not as efficiently as the rhesus monkey TRIM5alpha. In this application, we propose: 1) To identify the determinants of antiviral potency in primate TRIM5alpha proteins; 2) To understand the impact of interspecies variation in TRIM5alpha on the ability of the protein to restrict particular retroviruses; 3) To elucidate the mechanism of TRIM5alpha's potent antiviral effect.