HIV NEF FUNCTION

HIV NEF 功能

• 批准号: 6432822
• 负责人: Jon W Marsh
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432822
• 关键词: HIV infections; T lymphocyte; gene expression; host organism interaction; human immunodeficiency virus 1; human tissue; immunopathology; intracellular; leukocyte activation /transformation; macrophage; protein kinase; virus infection mechanism; virus protein

The objective of this study is to elucidate the intracellular interactions of the HIV regulatory protein Nef with host cell activities. Early in the HIV-1 infection of CD4 T cells this retrovirus expresses regulatory proteins, with the Nef transcript representing nearly 80% of total viral mRNA. In vivo infectivity by SIV and HIV is achieved in the absence of Nef expression, but there is an absolute requirement for Nef in the production of high viral titers. In the absence of Nef, there is loss of development of the immunological and neurological dysfunctions characteristic of AIDS. The essential activity of the Nef protein in the development of AIDS has not been defined. We have discovered that expression of Nef in human CD4 T cells results in a lowering of the activation threshold. Since activation is essential for viral synthesis, Nef thus has a direct role in increasing viral production. Evidence suggest that the biochemical site affected by Nef is early in the T cell receptor pathway. We had previously established that the Nef protein associates with a member of the p21-activated kinase (PAK) family, which is known to initiate activation pathways as well as alter cytoskeletal structures. An understanding of the biochemical activity of this virulence factor could lead to new options for treating HIV-infected individuals.

本研究的目的是阐明 HIV 调节蛋白 Nef 与宿主细胞活性的细胞内相互作用。在 HIV-1 感染 CD4 T 细胞的早期，这种逆转录病毒表达调节蛋白，其中 Nef 转录本占病毒总 mRNA 的近 80%。 SIV和HIV的体内感染性是在没有Nef表达的情况下实现的，但在产生高病毒滴度时对Nef有绝对的要求。 如果缺乏 Nef，艾滋病特有的免疫和神经功能障碍的发展就会受到阻碍。 Nef 蛋白在艾滋病发展中的基本活性尚未确定。 我们发现人类 CD4 T 细胞中 Nef 的表达会导致激活阈值降低。 由于激活对于病毒合成至关重要，因此 Nef 在增加病毒产量方面具有直接作用。 有证据表明，受 Nef 影响的生化位点位于 T 细胞受体途径的早期。 我们之前已经确定 Nef 蛋白与 p21 激活激酶 (PAK) 家族的成员相关，该家族已知可以启动激活途径并改变细胞骨架结构。 了解这种毒力因子的生化活性可能会为治疗艾滋病毒感染者提供新的选择。