IMMUNOLOGY AND MOLECULAR VIROLOGY OF ACUTE HIV INFECTION

该提案概述了一个跨学科的合作， 一组具有以下经验的高级临床研究者： 设计、招募、入组和保留急性 和早期艾滋病毒感染，以及一组经验丰富的基础科学 在细胞免疫学领域有专长的研究人员 以及艾滋病毒的分子病毒学。 该提案将 詹姆斯博士的实验室马林斯（华盛顿大学） 与华盛顿大学的5个临床合作点， 明尼苏达大学、日内瓦大学、纽 南威尔士和8个艾滋病毒网络疫苗准备点中的7个。 记录血清转化的核心病毒学检测， 监测体液和病毒学反应， 自然史和治疗研究将在 L博士的实验室科里（华盛顿大学），吕克博士 Perrin（日内瓦大学）和Haynes Sheppard博士 （加州州卫生部）。 统计和数据 管理支持将由弗雷德的史蒂文·赛尔夫博士指导。 哈钦森癌症研究中心。 参与研究小组的研究人员已经发表了超过 70篇关于原发性艾滋病毒的文章，所有的研究人员都有 与研究组PI Corey博士持续合作。 我们预计将招募45例急性和115例 早期（定义为自感染后150天）。 艾滋病毒/艾滋病网络合作小组的参与提供了一个 对最近感染艾滋病毒的患者进行基于人口的抽样调查< 尤其是那些有亚临床感染的人。 我们将评估 是否初始HIV-1特异性CD 8 T细胞应答， TCR库预测随后的疾病进展，2） 确定是否在急性和早期诱导HIV特异性包膜CTL 感染控制病毒载量和影响结果，或是否 病毒载量的变化与病毒的改变和识别有关， 自体菌株表达的表位或与 最小程度改变的病毒表位，3）确定是否选择性 在可检测到的免疫反应之前施加压力， 包膜基因是不同的，更严格的纯化比那些 应用于病毒基因组的其他区域，以及4）建立 临床试验网络，以识别，招募和保留患者， 临床和亚临床急性和早期HIV感染， 进行新型抗病毒治疗的I期试验。 提出 治疗试验包括1）评价联合 抗逆转录病毒疗法对HIV-1组织库的影响， 急性和早期艾滋病毒，2）减少T细胞的试点试验 泼尼松激活和同时抗逆转录病毒治疗 在早期艾滋病毒感染者中，以及3）一项三重 与双重组合抗逆转录病毒疗法相比， 早期艾滋病

This proposal outlines an interdisciplinary collaboration between a group of senior clinical investigators who have experience in the design, recruitment, enrollment, and retention of persons with acute and early HIV infection, and a group of experienced basic science researchers who have expertise in the field of cellular immunology and the molecular virology of HIV. The proposal links the laboratories of Dr. James I. Mullins (University of Washington) with 5 collaborating clinical sites at the University of Washing, University of Minnesota, University of Geneva, University of New South Wales, and 7 of the 8 HIVNET Vaccine Preparedness sites. The core virological assays to document seroconversion and monitor the humoral and virological response in the proposed natural history and treatment studies will be performed in the laboratories of Dr. L. Corey (University of Washington), Dr. Luc Perrin (University of Geneva), and Dr. Haynes Sheppard (California State Health Department). The statistical and data management support will be directed by Dr. Steven Self of the Fred Hutchinson Cancer Research Center. The investigators involved in the study group have published over 70 articles in the area of primary HIV and all the investigators have ongoing collaborations with Dr. Corey the PI of the Study Group. We anticipate enrolling 45 patients with acute and 115 patients with early (defined as 150 days from acquisition of infection) yearly. The involvement of the HIVNET collaborating groups provides a population based sampling of patients with recently acquired HIV< especially those with subclinical infection. We will evaluate whether initial HIV-1 specific CD8 T cell responses as measured by TCR repertoire are predictive of subsequent disease progression, 2) ascertain if HIV specific envelope CTL induced in acute and early infection control viral load and influence outcome or whether changes in viral load are associated with alterations and recognition of epitopes expressed by autologous strains or with antagonisms by minimally altered viral epitopes, 3) determine whether selective pressures applied prior to detectable immune responses to the envelope gene are distinct and more stringently purifying than those applied to other regions of the viral genome, and 4) establish a clinical trials network to identify, enroll and retain patients with clinical and subclinical acute and early HIV infection and to conduct pilot phase I trials of novel antiviral therapy. Proposed treatment trials include 1) an evaluation of combination antiretroviral therapy on the tissue reservoirs of HIV-1 among those with acute and early HIV, 2) a pilot trial of reducing T cell activation with prednisone and concurrent antiretroviral therapy among persons with early HIV, and 3) a phase II study of triple versus double combination antiretroviral therapy for the treatment of early HIV.