CYTOTOXIC LYMPHOCYTE RESPONSES IN ACUTE HIV1 INFECTION

急性 HIV1 感染中的细胞毒性淋巴细胞反应

• 批准号: 6378339
• 负责人: Robyn S Klein
• 金额: $ 16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378339
• 关键词: HIV infections; cell mediated lymphocytolysis test; cellular immunity; clinical research; clone cells; cytotoxic T lymphocyte; epitope mapping; human immunodeficiency virus 1; human subject; leukocyte activation /transformation; virus antigen

The factors responsible for the initial fall in viremia during acute HIV-1 infection are incompletely understood. The appearance of HIV-1 specific cytotoxic lymphocytes (CTL) has been temporally correlated with the decline in viremia, before the appearance of detectable neutralizing antibodies, suggesting that the cellular immune response may initially contain viral replication. Alternatively, mathematical modeling suggests that the decline in viremia is the result of expected population dynamics of a lymphotropic cytopathic retrovirus, and that the sharp decline in viremia is a result of diminished numbers of infectable activated CD4 cells. Almost all studies of CTL responses during primary infection have been limited to analysis of recognition of laboratory strains of virus, such that the breadth and specificity of the initial response is not known. Although recent longitudinal studies in a single person with primary infection suggest that CTL can exert immune pressure, as evidenced by the emergence of sequence variation within a dominant CTL epitope, the ability of CTL or CD8 cells to actually control replication of the initial virus present has not been demonstrated. I propose to perform a detailed analysis of the antiviral cellular immune response in primary HIV-1 infection. We have developed in vitro assays which allow for the direct examination of antiviral activity of CD8 cells and CTL clones. We are also developing an adapted novel technique for the rapid expression of PCR amplified virus genes using a combination of vaccinia infection-plasmid transfection, such that responses to autologous virus can be assessed efficiently. Using these techniques, I will conduct a detailed study of the antiviral activity of CTL and CD8 cells during the critical period of primary infection when the viral load is declining, in order to determine the contribution of the immune system to this decline. Through a cohort of persons with primary infection in Boston and through an established and functional collaboration with UCSF, we have access to blood and tissue specimens from persons during primary infection, prior to seroconversion and prior to the establishment of the viral set point. An analysis of the antiviral immune response in these individuals will provide important information regarding the correlates of protective immunity and help guide the design of therapeutic strategies and vaccines. Specifically, I propose to: 1. Characterize the magnitude, breadth and specificity of the CTL response to autologous virus in blood and tissues at the time of primary infection, when peak viremia is declining. 2. Determine the ability of CD8 cells and CTL clones to inhibit replication of autologous virus at the time of declining viremia during acute infection.

急性期病毒血症最初下降的因素 对HIV-1感染的认识还不完全。 HIV-1的出现 特异性细胞毒性淋巴细胞（CTL）与 在出现可检测的中和作用之前， 抗体，这表明细胞免疫反应最初可能 含有病毒复制。 或者，数学建模 表明病毒血症的下降是预期的结果， 嗜淋巴细胞性细胞病变逆转录病毒的群体动力学， 病毒血症的急剧下降是由于 活化的CD 4细胞。 几乎所有关于CTL应答的研究 在原发性感染期间，仅限于识别分析 实验室病毒株，这样的广度和特异性 最初的反应是未知的。虽然最近的纵向 对原发性感染的单个人的研究表明，CTL可以 施加免疫压力，正如序列的出现所证明的那样， 优势CTL表位内的变异，CTL或CD 8细胞 实际上控制最初病毒的复制， 被证明。 我建议对这一问题进行详细分析。 抗病毒细胞免疫应答在原发性HIV-1感染中的作用我们有 开发了体外试验，可以直接检查 CD 8细胞和CTL克隆的抗病毒活性。我们也在开发 一种用于快速表达PCR扩增的 使用牛痘感染-质粒组合的病毒基因 转染，使得可以评估对自体病毒的应答 有效地 利用这些技术，我将进行详细的研究 CTL和CD 8细胞的抗病毒活性在关键的 病毒载量下降的原发感染期， 以确定免疫系统对这种下降的贡献。 通过一组波士顿原发性感染者， 与UCSF建立了有效的合作，我们可以访问 在初次感染期间从人身上采集的血液和组织样本， 在血清转化之前和病毒集建立之前 点 分析这些患者的抗病毒免疫应答， 个人将提供有关相关因素的重要信息 保护性免疫力，并帮助指导治疗设计 战略和疫苗。 具体而言，我建议：1。表征 CTL对自体免疫的应答的幅度、广度和特异性 初次感染时血液和组织中的病毒， 病毒血症正在减少。 2.测定CD 8细胞和CTL的能力 克隆，以抑制自体病毒的复制， 在急性感染期间减少病毒血症。