CTL RESPONSE IN ACUTE HIV INFECTION

急性 HIV 感染中的 CTL 反应

• 批准号: 2886125
• 负责人: JOIA S MUKHERJEE
• 金额: $ 9.02万
• 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: 1998-07-15 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2886125
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; cellular immunity; clinical research; cytotoxic T lymphocyte; epitope mapping; helper T lymphocyte; human immunodeficiency virus 1; human subject; leukocyte activation /transformation; lymphocyte proliferation; microorganism immunology; tissue /cell culture

Acute HIV-1 infection is characterized by high level viremia, which subsequently declines to a quasi set-point. During the earliest stages of infection the majority of persons will develop an infectious mono- like syndrome with variable combinations of fever, rash, pharyngitis, oral and genital ulcers. Historically the majority of such cases have not been diagnosed, largely because of the non-specific nature of the symptoms and the lack of readily available assays to reliably diagnose the acute infection. The advent of viral load measurements has faciliated the early diagnosis of acute HIV infection, and the availability of highly active antiretroviral therapy has provided the opportunity to intervene therapeutically at the early stage of infection. Studies of acutely infected persons have indicated that the initial drop in viremia is temporally associated with the appearance of CTL, but these studies have been limited in number such that the breadth specificity of the CTL response in early infection is imcompletely understood. Furthermore, studies of the effects of early antiviral therapy on the ontogeny of the immune response have not been performed. Recent studies in the host laboratory have shown that early antiretroviral intervention results in the restoration of HIV-1-specific CD4 proliferative responses to both p24 and gp160. Since virus-specific CD4 cells are essential for maintenance of CTL responses in chronic viral infections, it is essential to determine not only the CTL response to HIV during acute infection, but also the effects of early therapy on this response. To address the immunopathogenesis of acute HIV infection, the AIDS Research Center at Massachusetts General Hospital has identified a cohort of 9 individuals with acute HIV infection. The hypothesis to be tested in the present proposal is that early antiviral therapy during acute HIV infection will be associated with preserved and improved CTL responses to HIV. The availability of this cohort of acutely infected patients affords the unique opportunity to study the immunology of primary HIV infection. To test this hypothesis a series of experiments will be performed to: 1) Characterize the magnitude and breadth of the CTL response in primary infection in acutely infected patients and compare these results with the CTL responses in acutely infected patients who were not treated with HAART; 2) Define the relationship of the CTL response with the development of CD4 help and the diminution of viral load; 3) Characterize the epitope specificity of CTL responses in primary HIV infection by cloning specifically stimulated CD8 cells; 4) Examine the ability of CTL responses elicited during acute infection to inhibit viral replication. These studies will provide important information regarding the immune mechanisms contributing to control of HIV replication during acute HIV infection.

急性HIV-1感染的特征是高水平的病毒血症， 随后下降到准设定点。 在早期阶段 大多数人会发展成传染性单核细胞增多症， 比如发热、皮疹、咽炎 口腔和生殖器溃疡。 从历史上看，大多数此类案件 未被诊断，主要是因为其非特异性 症状和缺乏现成的检测方法来可靠地诊断 急性感染。 病毒载量测量的出现 有助于急性艾滋病毒感染的早期诊断， 高活性抗逆转录病毒疗法的可用性提供了 在早期阶段进行治疗干预的机会 感染 对急性感染者的研究表明， 病毒血症的最初下降与以下症状的出现有时间相关性： CTL，但这些研究在数量上有限， 在早期感染中CTL应答的特异性不完全 明白 此外，研究早期抗病毒药物的作用， 尚未进行对免疫应答的个体发生的治疗。 最近在宿主实验室的研究表明， 抗逆转录病毒干预导致HIV-1特异性 对p24和gp 160的CD 4增殖反应。 由于病毒特异性 CD 4细胞对维持慢性淋巴细胞白血病患者的CTL应答至关重要。 病毒感染时，不仅要确定CTL， 艾滋病病毒在急性感染期间的反应，而且还影响早期 治疗这个反应。 为了解决急性胰腺炎的免疫发病机制， 艾滋病毒感染，艾滋病研究中心在马萨诸塞州一般 医院已经确定了一个队列的9个人与急性艾滋病毒 感染 本提案中有待检验的假设是， 急性HIV感染期间的早期抗病毒治疗将与 保留并改善了对HIV的CTL反应。 的可用性 这群急性感染患者提供了独特的机会， 研究原发性HIV感染的免疫学。 为了验证这一 假设将进行一系列实验以：1）表征 在原发感染中CTL应答的幅度和宽度 急性感染患者，并将这些结果与CTL进行比较， 未接受HAART治疗的急性感染患者的反应; 2)定义CTL应答与以下发展的关系： CD 4辅助和病毒载量的减少; 3）表征表位 通过克隆研究HIV原发感染中CTL应答的特异性 特异性刺激的CD 8细胞; 4）检测CTL的能力 在急性感染期间引起的抑制病毒复制的反应。 这些研究将提供有关免疫的重要信息。 在急性HIV感染期间有助于控制HIV复制的机制 感染