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感染的早期事件可能决定了随后的疾病进程。因此，需要对人类感染的急性阶段进行全面研究，这对于更好地了解免疫保护的相关关系至关重要，而且可能对开发有效的疫苗和免疫疗法也极为重要。有意义的见解最有可能需要对大量急性感染者进行研究。为此，我们在两个小组（波士顿和悉尼）之间建立了合作，每个小组在识别急性艾滋病毒感染者方面都有丰富的经验，并且有记录的能力将这些受试者纳入发病机制和干预试验。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之间的联系；3)急性感染早期治疗可增强关键CD4细胞免疫应答；4)证明这种早期干预至少可以在治疗中断后暂时增强免疫控制；5)免疫选择压力影响病毒进化和传播。然而，主要问题仍有待解决，最好在更大规模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，详细研究与急性HIV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、招募和随访急性和早期艾滋病毒感染者；2)利用未接受治疗的受试者开展HIV发病机制研究，以确定HIV感染中病毒控制的基本免疫学相关因素；3)启动随机治疗研究，从临床和病毒学角度检验操纵急性感染者免疫反应的效果；4)对急性感染的治疗对象进行相应的发病机制研究，确定治疗对免疫和病毒学因子的影响。

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.