Antiretroviral Activity of TRIM5alpha

性状（由申请方提供）：逆转录病毒进入宿主细胞后，可在某些种属的细胞中被显性作用宿主因子阻断。例如，人类免疫缺陷病毒（HIV-1），获得性免疫缺陷综合征（AIDS）的病原体，在大多数旧大陆猴子的细胞中遇到进入后阻滞。相比之下，相关的猿免疫缺陷病毒（SIV）的感染仅限于新世界猴。某些鼠白血病病毒株（MLV）进入人类细胞，但随后很快被阻断。所有这些进入后限制具有共同的特征：1）阻断发生在逆转录之前或早期; 2）病毒对限制的易感性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性衣壳的病毒样颗粒竞争。在恒河猴中限制HIV-1的因子被确定为TRIM 5 α。人类直系同源物也可以抑制HIV-1感染，但不如恒河猴TRIM 5 α有效。在本申请中，我们提出：1）确定灵长类动物TRIM 5 α蛋白抗病毒效力的决定因素; 2）了解TRIM 5 α的种间变异对蛋白限制特定逆转录病毒能力的影响; 3）阐明TRIM 5 α有效抗病毒作用的机制。

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.