Pathogenesis of Clade C HIV Infection

描述（由申请人提供）：经过近30年的集中研究努力，有效的艾滋病毒疫苗仍然是一个难以实现的目标。尽管在产生疫苗诱导的T细胞和B细胞反应方面取得了成功，但目前还没有领先的候选疫苗。到目前为止的证据表明，T细胞和B细胞反应都需要广泛的群体疗效，既可以防止最初的局部组织感染完全建立，也可以在感染发生时调节病毒血症。为此，确定hiv特异性CD8 T细胞反应的效应臂仍然至关重要，这无疑是与病毒控制最密切相关的一个免疫参数。此外，由于疫苗研究将最有效地在新感染高发地区进行，因此掌握这些人群中流行的病毒种类以及感染后产生的免疫反应的综合数据至关重要。在这笔赠款的过去供资期内，我们在非洲流行病的核心领域取得了重大进展，建立了急性和慢性艾滋病毒感染者的队列，并利用这些队列开始确定T细胞反应的免疫原性、特异性、免疫遗传学和功能。我们的数据表明，在体内和体外，并非所有hiv特异性CD8 T细胞应答都有助于控制病毒血症。此外，在急性感染中，在病毒血症下降最迅速的时期，尽管在感染菌株中存在同源表位，但在慢性感染中成为靶标的表位中只有一小部分成为靶标，而且这些表位中只有一小部分似乎施加免疫选择压力。这一竞争性更新的目标是在本赠款最初供资期间取得进展所奠定的坚实基础上，对急性感染关键时期针对艾滋病毒的有效和无效免疫反应进行全面分析，目标是确定哪些反应最需要用保护性疫苗诱导，哪些序列最重要需要纳入有效的免疫原。具体而言，我们建议(1)确定急性HIV-1感染中HIV-1特异性CD8+ T细胞反应的特异性和功能抑制能力(2)通过对血清转化前鉴定的受试者进行深度测序，确定急性HIV-1进化枝C病毒感染中应用的免疫选择压力的演变及其对病毒适应度的影响(3)确定急性进化枝C病毒感染中定义有效和无效CD8 T细胞反应的功能特征

DESCRIPTION (provided by applicant): After nearly 3 decades of concentrated research efforts, an effective HIV vaccine remains an elusive goal. Despite successes in generating vaccine induced T and B cell responses, there are no lead vaccine candidates currently in the pipeline. Evidence thus far suggests that both T and B cell responses will be required for broad-based population efficacy, both to prevent an initial localized tissue infection from becoming fully established and to modulate viremia should infection occur. To this end, it remains critical to define the effector arm of the HIV-specific CD8 T cell response, which is without question the one immune parameter that is most strongly associated with viral control. In addition, since vaccine studies will most effectively be performed in areas of high incidence of new infection, it will be critical to have comprehensive data regarding the circulating viral species in these populations, and the immune responses generated upon infection. Over the past funding period of this grant, we have made significant progress, working at the heart of the African epidemic, in establishing cohorts of persons with acute and chronic HIV infection, and using these to begin to define the immunogenicity, specificity, immunogenetics and function of the T cell response. Our data inidicate that ot all HIV-specific CD8 T cell responses contribute to control of viremia in vitro and in vivo. Moreover, in acute infection, during the most rapid decline in viremia, only a fraction of epitopes that become targeted in chronic infection are targeted, despite the presence of the cognate epitope in the infecting strain, and only a fraction of these appear to exert immune selection pressure. The goal of this competing renewal is to build on the firm foundation laid by progress during initial funding period of this grant to perform a comprehensive analysis of effective and ineffective immune responses against HIV during the critical period of acute infection, with the goal of defining those responses most important to induce with a protective vaccine, and those sequences most important to incorporate into an effective immunogen. Specifically, we propose to (1) determine the specificity and functional inhibitory capacity of HIV-1-specific CD8+ T cell responses in acute HIV-1 infection (2) Define the evolution of immune selection pressure applied in acute HIV-1 clade C virus infection by deep sequencing of subjects identified prior to seroconversion, and the impact on viral fitness and (3) Define the functional characteristics that define effective and ineffective CD8 T cell responses in acute clade C virus infection