Immunopathogenesis of Acute HIV-1 Infection

描述(申请人提供)：在这项建议中，我们概述了研究急性和早期HIV-1感染的免疫发病机制的计划，使用抗逆转录病毒化疗药物和治疗性疫苗的顺序治疗干预措施，试图操纵病毒与宿主的相互作用，使宿主受益。我们的团队包括美国(丹佛和亚特兰大)、巴西和津巴布韦的临床站点，以及科罗拉多大学、明尼苏达大学和拉什医学院的实验室研究人员互动小组。我们计划将30名急性感染的患者和90名早期感染艾滋病毒的患者纳入一项随机临床试验的综合计划，该计划将包括及早启动有效的化疗组合抗逆转录病毒方案，旨在最大限度地提高耐受性、便利性和依从性，并将毒性降至最低。研究参与者达到无法检测到的血浆HIV-1 RNA水平将被允许进入治疗性疫苗的受控临床试验，使用几种旨在最大限度提高病毒特异性细胞免疫的不同疫苗方法。治疗干预的影响将根据治疗中断后宿主效应机制控制病毒复制的程度来评估。在这些连续治疗干预措施的背景下，将通过一系列协调的实验室研究来深入评估急性HIV-1感染的免疫发病机制，这些研究将评估细胞和体液HIV-1特异性效应机制和可溶性介质在控制血浆和淋巴组织中的HIV-1表达以及在建立病毒复制控制后促进免疫重建方面的作用。还将对病毒适应性和多样性的作用进行研究。这些调查的目标是更好地了解急性HIV-1感染背景下的病毒-宿主相互作用，改进HIV-1感染的治疗方法，并提供将被证明对艾滋病疫苗开发有用的见解。

DESCRIPTION (provided by applicant): ln this proposal we outline plans to investigate the immunopathogenesis of acute and early HIV-1 infection using sequential therapeutic interventions with antiretroviral chemotherapeutic agents and therapeutic vaccination in an attempt to manipulate the virus-host interaction to the benefit of the host. Our group consists of clinical sites in the United States (Denver arid Atlanta), Brazil and Zimbabwe and an interactive group of laboratory investigators based at the Universities of Colorado and Minnesota and at Rush Medical School. We plan to enroll 30 acutely infected and 90 patients with early HIV infection into an integrated program of randomized clinical trials that will feature early initiation of potent chemotherapeutic combination antiretroviral regimens designed to maximize tolerability, convenience and adherence and to minimize toxicity. Study participants achieving undetectable levels of plasma HIV-1 RNA will be offered entry into controlled clinical trials of therapeutic vaccination using several different vaccine approaches designed to maximize virus specific cellular immunity .The impact of therapeutic interventions will be evaluated by the extent to which viral replication is controlled by host effector mechanisms following therapeutic interruption. The immunopathogenesis of acute HIV-1 infection will be intensively evaluated in the context of these sequential therapeutic interventions by a coordinated series of laboratory studies that will evaluate the role of cellular and humoral HIV-1 specific effector mechanisms and soluble mediators in controlling HIV-1 expression in plasma and lymphoid tissues and in facilitating immune reconstitution following establishment of control of viral replication. Studies of the role of viral fitness and diversity will also be undertaken. The goals of these investigations are to better understand virus-host interactions in the context of acute HIV-1 infection, to improve therapeutic approaches to HIV-1 infection and to provide insights that will prove useful in AIDS vaccine development.