HIV Infection of Non-Dividing Cells

非分裂细胞的 HIV 感染

• 批准号: 7879997
• 负责人: Michael Emerman
• 金额: $ 29.4万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879997
• 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）和其他慢病毒感染了与细胞周期进展无关的细胞，但是诸如鼠白血病病毒（MLV）等γ型病毒需要通过明星膜传播细胞。以前已经假设，艾滋病毒元素的核进口特性是艾滋病毒和其他仅在有丝分裂后进入核的逆转录病毒之间的主要差异。然而，最近的数据表明，衣壳（CA）蛋白而非核进口蛋白是逆转录病毒感染非分散细胞能力的主要决定因素。在这里，我们将确定测试CA负责HIV的这一重要特性的模型，我们将表征CA在病毒生命周期中影响早期事件的机制。在该提案中，HIV-1 Ca中具有特异性突变的HIV将以感染非分裂细胞（例如细胞周期滞留细胞，原代巨噬细胞和部分激活的T细胞）的能力来表征。特别是，我们将集中于CA的N末端结构域中的一组氨基酸，即初步数据表明对HIV感染非分裂细胞的能力具有深远的影响。然后，我们将确定通过测试未涂层是感染非分裂细胞的速率限制步骤的假设，并检查病毒核酸的核进入是否影响非生动细胞的核进入，从而确定影响了这些HIV-1 CA突变体的病毒生命周期的阶段。在被感染者中是HIV的许多细胞，以及被认为是传播时被感染的第一个细胞，这些细胞被认为是无扩散的。因此，HIV感染非分散细胞的特性使其可以扩散到主要病毒储层位点，例如未激活的CD4+ T细胞和末端分化的巨噬细胞。允许其进入非分散细胞的精确病毒决定因素的鉴定可能会呈现针对HIV的新药物靶标。