CELLULAR TROPISM OF A BRAIN DERIVED HIV-1 ISOLATE

脑源性 HIV-1 分离株的细胞趋向性

• 批准号: 2065296
• 负责人: William D. O'Brien
• 金额: $ 10.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2065296
• 关键词: AIDS; genetic manipulation; genetic mapping; genetic strain; host organism interaction; human immunodeficiency virus 1; human tissue; macrophage; monoclonal antibody; nervous system infection; nucleic acid sequence; polymerase chain reaction; site directed mutagenesis; virus replication

Neurologic impairment is now a well-recognized symptom of the acquired immunodeficiency syndrome (AIDS); many of the central nervous system (CNS) abnormalities appear to be a direct result of infection of cells of the mononuclear phagocyte lineage by human immunodeficiency virus type 1 (HIV- 1). These cells are susceptible to productive infection by some but not all HIV-1 isolates. It is of importance to identify the viral function(s) responsible for the observed differences in HIV-1 cellular tropism. The overall goal of the proposed research is to understand the mechanism of HIV-1 tropism for mononuclear phagocytes. REplication of a cloned macrophage-tropic cells, reverse transcription, integration, and virus- specific RNA production in peripheral blood lymphocytes and mononuclear phagocytes. These properties will be compared with those of HIV-1 isolates having differing abilities to productively infect mononuclear phagocytes in order to identify the stages of the HIV-1 life-cycle blocked in infection with non-tropic isolates (Aim 1). To identify viral genes or sequences responsible for mononuclear phagocyte tropism, molecular recombinants will be constructed between cloned isolates with differing abilities to replicate in these cells (Aim 2). Preliminary experiments using parental and recombinant HIV-1 strains suggest that HIV-1 strains unable to productively infect mononuclear phagocytes appear to be blocked at entry. Binding and penetration assays (Aim 3) will be used to delineate how entry is involved in infection with strains poorly tropic for mononuclear phagocytes. An understanding of precise viral mechanisms for tropic effects of HIV-1 in mononuclear phagocytes will suggest strategies to interfere with virus replication in these cells. Studies such as these may allow one to interfere with the entry of HIV-1 from the blood into the CNS via mononuclear phagocytes and reach the ultimate goal of reducing the prevalence of neurologic complications of AIDS.

神经功能障碍现已成为获得性神经病的一个公认的症状 免疫缺陷综合症（艾滋病）；许多中枢神经系统 (CNS) 异常似乎是细胞感染的直接结果 人类免疫缺陷病毒 1 型（HIV- 1）。 这些细胞容易受到某些细胞的生产性感染，但并非如此 所有 HIV-1 分离株。识别病毒功能非常重要 造成了所观察到的 HIV-1 细胞趋向性差异。 拟议研究的总体目标是了解 HIV-1 对单核吞噬细胞的趋向性。 克隆的复制 嗜巨噬细胞、逆转录、整合和病毒- 外周血淋巴细胞和单核细胞中特异性 RNA 的产生 吞噬细胞。 这些特性将与 HIV-1 分离株的特性进行比较 具有不同的能力来有效感染单核吞噬细胞 以确定 HIV-1 生命周期在感染过程中受阻的阶段 与非热带分离株（目标 1）。 鉴定负责单核吞噬细胞的病毒基因或序列 向性，将在克隆分离株之间构建分子重组体 在这些细胞中具有不同的复制能力（目标 2）。 初步的 使用亲本和重组 HIV-1 毒株进行的实验表明，HIV-1 无法有效感染单核吞噬细胞的菌株似乎是 入口处被堵住。 结合和渗透测定（目标 3）将用于 描述进入如何参与对热带性较差的菌株的感染 单核吞噬细胞。 了解 HIV-1 热带效应的精确病毒机制 单核吞噬细胞将提出干扰病毒的策略 在这些细胞中进行复制。 诸如此类的研究可能会让人们 干扰 HIV-1 从血液进入中枢神经系统 从而达到减少单核吞噬细胞的最终目的 艾滋病神经系统并发症的患病率。