IMMUNOLOGY AND MOLECULAR VIROLOGY OF ACUTE HIV INFECTION

该提案概述了一种跨学科协作 有经验的高级临床研究人员组成的小组 设计、招聘、招生和留住有急性呼吸道疾病的人员 和早期的艾滋病毒感染，以及一群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·I·穆林斯博士的实验室(华盛顿大学) 与洗涤大学的5个临床站点合作， 明尼苏达大学、日内瓦大学、纽约大学 南威尔士，以及8个HIVNet疫苗准备地点中的7个。 记录血清转换的核心病毒学分析和 监测建议的体液和病毒学反应 自然病史和治疗研究将在 L.Corey博士(华盛顿大学)、Luc博士的实验室 佩林(日内瓦大学)和海恩斯·谢泼德博士 (加利福尼亚州卫生局)。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。 参与研究小组的调查人员已经发表了 70篇关于原发艾滋病毒领域的文章，所有的研究人员都 正在与科里博士进行合作，科里博士是研究小组的PI。 我们预计招募45名急性白血病患者和115名急性白血病患者。 每年的早期(定义为感染后150天)。 HIVNet合作小组的参与提供了一个 以人群为基础的新近感染艾滋病毒患者的抽样； 尤其是那些亚临床感染的患者。我们将评估 是否最初的HIV-1特异性CD8 T细胞反应由 TCR谱系可预测随后的疾病进展，2) 确定HIV特异性包膜CTL在急性和早期是否被诱导 感染控制病毒载量并影响结局或 病毒载量的变化与改变和识别有关 由自体菌株表达的表位或由 改变最小的病毒表位，3)决定是否选择性 在可检测的免疫反应之前施加的压力 包膜基因是独特的，比那些 应用于病毒基因组的其他区域，以及4)建立一个 临床试验网络，以识别、招募和保留患有 临床和亚临床的急性和早期艾滋病毒感染以及 进行新型抗病毒疗法的试点I期试验。建议 治疗试验包括1)联合治疗的评估 其中HIV-1组织贮备库的抗逆转录病毒治疗 对于急性和早期艾滋病毒，2)减少T细胞的试点试验 强的松激活联合抗逆转录病毒治疗 在早期艾滋病毒携带者中，以及3)TRIPLE的II期研究 与双重联合抗逆转录病毒治疗的对比 早期的艾滋病病毒。

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.