Immunopathogenesis of acute and early HIV infection

描述（由申请人提供）：本计划项目申请的标题是：急性和早期HIV感染的免疫发病机制。该计划将包括由2个核心设施支持的4个项目。该计划还将得到纽约大学CFAR的免疫学，病毒学和临床支持（生物免疫学-流行病学）核心的基础设施的支持，并将严重依赖艾滋病临床试验部门的资源。该计划将是高度集成的，因为一些研究人员将在多个项目中工作，并且将在不同的项目中对同一患者同时获得的样本进行实验，以便于解释结果。所有结果将被输入到一个共同的数据库开发的前沿科学。 每个项目将以不同的方式解决为什么在治疗延迟的受试者中失去或不诱导对HIV抗原的强CD 4反应性的总体问题。 免疫反应控制了几乎所有在最初几天内不致命的病毒感染，但对HIV的长期有效免疫控制发生在少数感染者中。艾滋病毒阻碍建立有效免疫反应的机制尚不清楚，但必须在感染的最早阶段起作用。这些机制可能包括树突状细胞抗原呈递过程的故障，T细胞的不适当的过度活化和凋亡，或对HIV抗原应答的CD 4克隆的缺失或无应答。低病毒载量的长期无进展者维持对HIV抗原的淋巴细胞增殖反应（LPR），这是一种记忆反应，而大多数已建立感染的个体即使在抗逆转录病毒治疗抑制病毒载量后也缺乏对HIV抗原的强LPR。我们的假设是，未能发展和维持记忆CD 4对HIV抗原的反应是一个关键的病理过程中，HIV感染。 该计划将利用纽约大学/贝尔维尤分校和我们的附属医院发现的大量急性和早期艾滋病毒感染，以及大量类似的个人。(At目前，纽约大学/贝尔维尤分校与加州大学圣地亚哥分校并列为ACTG原发性HIV感染研究的最高注册人数。我们还将跟踪急性感染风险极高的人群，如果发生感染，我们将在感染前获得有活力的冷冻细胞。

DESCRIPTION (provided by applicant): The title of this Program Project application is: Immunopathogenesis of Acute and Early HIV Infection. The program will consist of 4 projects supported by 2 core facilities. The program also will be supported by the infrastructures of the immunology, virology and clinical support (biostatistics-epidemiology) cores of the NYU CFAR and will rely heavily on resources within the AIDS Clinical Trials Unit. The program will be highly integrated in that some investigators will be working on more than one of the projects, and experiments will be performed in different projects on samples obtained at the same time from the same patients to facilitate interpretation of the results. All results will be entered into a common data-base developed by Frontier Science. The overall question of why strong CD4 reactivity to HIV antigens is lost or is not induced in subjects in whom treatment is delayed will be addressed in different ways by each of the projects. Immune responses control almost all viral infections that are not lethal during the first few days, yet long-term effective immunological control of HIV occurs in a small minority of infected individuals. The mechanisms by which HIV blocks the establishment of effective immune responses are not clear, but must be operative at the earliest stages of the infection. These mechanisms may include malfunctioning of the antigen presentation process by dendritic cells, inappropriate hyperactivation of T cells and apoptosis, or deletion or unresponsiveness of CD4 clones responsive to HIV antigens. Long-term nonprogressors with a low viral load maintain lymphocyte proliferative responses (LPR) to HIV antigens, a memory response, whereas the majority of individuals with established infection lack strong LPR to HIV antigens even after suppression of viral load with antiretroviral therapy. Our hypothesis is that the failure to develop and maintain memory CD4 responses to HIV antigens is a pivotal pathologic process in HIV infection. This program will take advantage of the large numbers of acute and early HIV infections being identified at NYU/Bellevue and our affiliated hospitals, combined with the large numbers of similar individuals. (At present NYU/Bellevue is tied with UCSD for top enrollment into the ACTG study of primary HIV infection.) We also will follow the cohort of individuals who are at exceedingly high risk of acute infection for whom we will have viably frozen cells obtained prior to infection should it occur.