Antiretroviral Activity of TRIM5alpha

TRIM5alpha 的抗逆转录病毒活性

• 批准号: 7008488
• 负责人: JOSEPH G SODROSKI
• 金额: $ 41.75万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-17 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008488
• 关键词: Macaca mulatta; Retroviridae; animal genetic material tag; biochemical evolution; gene expression; gene mutation; host organism interaction; human genetic material tag; human immunodeficiency virus 1; human subject; immunity; immunogenetics; microorganism immunology; protein structure; protein structure function; species difference; tissue /cell culture; transport proteins; virus genetics

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.

描述（由申请人提供）：逆转录病毒进入宿主细胞后，可以通过主导作用的宿主因子在某些物种的细胞中被阻断。例如，人类免疫缺陷病毒（HIV-1），即获得性免疫缺陷综合症（AIDS）的病原体，在大多数旧世界猴子的细胞中遇到了进入后阻塞。相比之下，相关的猿猴免疫缺陷病毒（SIV）的感染在新世界猴中受到限制。某些鼠白血病病毒 (MLV) 毒株会进入人体细胞，但很快就会被阻止。所有这些进入后限制都有共同的特征：1）阻断发生在逆转录之前或早期阶段； 2) 病毒对限制性敏感的决定因素是衣壳蛋白； 3)宿主细胞限制因子可以与含有限制性衣壳的病毒样颗粒竞争。恒河猴中限制 HIV-1 的因素已被确定为 TRIM5alpha。人类直系同源物也可以抑制 HIV-1 感染，但不如恒河猴 TRIM5alpha 有效。在此应用中，我们建议：1) 确定灵长类 TRIM5alpha 蛋白抗病毒效力的决定因素； 2) 了解TRIM5α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强效抗病毒作用的机制。