PATHOGENESIS AND TREATMENT OF ACUTE HIV INFECTION

描述（由申请人提供）：越来越多的证据表明，急性HIV感染的最早期事件可能定义了随后的病程。因此，需要对人类感染的急性阶段进行全面研究，这对于更好地理解免疫保护的相关性至关重要，并且对于开发有效的疫苗和免疫疗法也可能极其重要。最有可能需要对大量急性感染者进行研究才能得出有意义的见解。为此，我们建立了两个小组（波士顿和悉尼）之间的合作，每个小组在识别急性HIV感染者方面都有丰富的经验，并有记录证明有能力在发病机制和干预试验中招募这些受试者。这些研究者的贡献包括：1）首次证明急性感染与提示诊断的临床综合征相关; 2）急性感染症状的严重程度与感染的长期进展相关; 3）证明急性感染的早期治疗可增强关键的CD 4细胞免疫应答; 4）证明这种早期干预至少可以暂时增强治疗中断后的免疫控制;和5）免疫选择压力影响病毒进化和传播。然而，主要的问题仍然有待解决，最好在更大的队列研究的背景下解决。为了有效地解决这些问题，我们建议联合起来，详细调查与急性艾滋病毒感染的诊断、发病机制和治疗有关的问题。具体而言，我们建议：1）建立网络，以识别、招募和跟踪急性和早期艾滋病毒感染者; 2）利用未接受治疗的受试者进行艾滋病毒发病机制研究，以确定艾滋病毒感染中病毒控制的基本免疫相关性;第三章启动随机治疗研究，以检查在急性胰腺炎患者中操纵免疫应答的临床和病毒学效果。感染;和4）对患有急性感染的治疗对象进行相应的发病机制研究，并确定治疗对免疫学和病毒学因素的影响。

DESCRIPTION (provided by applicant): Increasing evidence indicates that the earliest events in acute HIV infection likely define the subsequent course of disease. Thus, the need for comprehensive studies of the acute stage of infection in humans is critical for a better understanding of the correlates of immune protection and is likely to also be extremely important for the development of effective vaccines and immunotherapies. Meaningful insights are most likely to require study of large groups of persons with acute infection. To this end, we have established collaboration between two groups (Boston and Sydney), each with extensive experience in identifying persons with acute HIV infection and with documented ability to enroll such subjects in pathogenesis and intervention trials. Contributions from these investigators include 1) the first demonstrations that acute infection is associated with a clinical syndrome suggesting the diagnosis; 2) the linking of severity of acute infection symptoms to long-term progression of infection; 3) the demonstration that early treatment of acute infection enhances critical CD4 cellular immune responses; 4) the demonstration that such early intervention can at least transiently enhance immune control following treatment interruption; and 5) that immune selection pressure influences viral evolution and transmission. However, major questions remain to be addressed and are best addressed in the context of larger cohort studies. To effectively address these questions, we propose to join forces and investigate in detail issues related to the diagnosis, pathogenesis and treatment of acute HIV infection. Specifically, we propose to 1 ) establish networks to identify, recruit and follow-up persons with acute and early HIV infection; 2) conduct HIV pathogenesis studies using subjects who have not undergone treatment to determine the fundamental immunological correlates of viral control in HIV infection; 3) initiate randomized treatment studies to examine the effect both clinically and virologically of manipulating the immune responses in persons with acute infection; and 4) conduct corresponding pathogenesis studies on treated subjects with acute infection and determine the impact of therapy on immunologic and virologic factors.