HIV Infection of Non-Dividing Cells

非分裂细胞的 HIV 感染

• 批准号: 7638581
• 负责人: Michael Emerman
• 金额: $ 29.7万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638581
• 关键词: Affect; Amino Acids; Be++ element; Beryllium; CD4 Positive T Lymphocytes; Capsid; Capsid Proteins; Cell Cycle Arrest; Cell Cycle Progression; Cells; Data; Drug Delivery Systems; Event; Gammaretrovirus; HIV; HIV-1; Infection; Interphase Cell; Mitosis; Modeling; Murine leukemia virus; Mutation; N-terminal; Nuclear; Nuclear Import; Nucleic Acids; Proliferating; Property; Proteins; Retroviridae; Site; Staging; Subfamily lentivirinae; T-Lymphocyte; Testing; Viral; Virus; Virus Diseases; interest; macrophage; mutant; transmission process

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) and other lentiviruses infect cells independent of cell- cycle progression, but gammaretroviruses such as the murine leukemia virus (MLV) require passage of cells through mitosis. Previously it had been hypothesized that nuclear import properties of HIV elements were the major difference between HIV and other retroviruses that only enter the nuclear after mitosis. However, recent data indicates that the capsid (CA) protein, and not nuclear import proteins, is the major determinant of the ability of a retrovirus to infect non-dividing cells. Here, we will definitively test the model that CA is responsible for this important property of HIV and we will characterize the mechanism whereby CA influences early events in the viral lifecycle. In this proposal, HIV with specific mutations in HIV-1 CA will be characterized for their ability to infect non-dividing cells such as cell-cycle arrested cells, primary macrophages, and partially activated T cells. In particular, we will concentrate on a set of amino acids in the N-terminal domain of CA that preliminary data suggest have a profound effect on the ability of HIV to infect non- dividing cells. We will then determine the stage of the virus lifecycle that is affected these HIV-1 CA mutants by testing the hypothesis that uncoating is the rate-limiting step for infection of non-dividing cells, and by examining if the nuclear entry of viral nucleic acids is affected in non-dividing cells. Many of the cells that are targets of HIV in infected people, as well as the first cells thought to be infected upon transmission, turn out to be non-proliferating. Thus, the property of HIV to infect non-dividing cells allows it to spread to major viral reservoirs sites such as non-activated CD4+ T cells and terminally differentiated macrophages. The identification of the precise viral determinants that allow it access to non-dividing cells may present new drug targets against HIV.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）和其他慢病毒感染细胞独立于细胞周期进展，但γ -逆转录病毒如小鼠白血病病毒（MLV）需要通过细胞有丝分裂传代。以前人们假设HIV元件的核输入特性是HIV与其他逆转录病毒之间的主要区别，逆转录病毒只在有丝分裂后进入细胞核。然而，最近的数据表明，衣壳（CA）蛋白，而不是核输入蛋白，是逆转录病毒感染非分裂细胞能力的主要决定因素。在这里，我们将明确地测试CA对HIV的这一重要特性负责的模型，我们将描述CA影响病毒生命周期早期事件的机制。在这一提议中，HIV-1 CA中具有特定突变的HIV将以其感染非分裂细胞（如细胞周期阻滞细胞、原代巨噬细胞和部分活化的T细胞）的能力为特征。特别是，我们将集中研究CA n端结构域的一组氨基酸，初步数据表明，这些氨基酸对HIV感染非分裂细胞的能力有深远的影响。然后，我们将通过测试剥离是非分裂细胞感染的限速步骤的假设，并通过检查病毒核酸的核进入是否在非分裂细胞中受到影响，来确定影响这些HIV-1 CA突变体的病毒生命周期阶段。在被感染的人体内，许多作为HIV目标的细胞，以及被认为在传播时被感染的第一批细胞，结果是不增殖的。因此，HIV感染非分裂细胞的特性使其能够扩散到主要的病毒库位点，如非活化的CD4+ T细胞和终分化的巨噬细胞。对病毒决定因子的精确识别，使其能够进入非分裂细胞，可能会提供新的药物靶点来对抗艾滋病毒。