Pathogenesis of Clade C HIV Infection

描述(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。尽管在疫苗诱导的T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在研制中。到目前为止的证据表明，T和B细胞的反应将是广泛的人群疗效所必需的，这既是为了防止最初的局部组织感染完全确立，也是为了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，毫无疑问，这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，因此获得关于这些人群中传播的病毒种类以及感染后产生的免疫反应的全面数据将是至关重要的。在这笔赠款的过去供资期间，我们在非洲疫情的核心地区取得了重大进展，建立了急性和慢性艾滋病毒感染者队列，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，在体外和体内，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，在病毒血症最迅速下降的时期，尽管感染株中存在同源表位，但只有一小部分成为慢性感染靶点的表位是靶标，而且其中只有一小部分似乎施加了免疫选择压力。这一竞争性更新的目标是在这笔赠款的初始资助期内取得进展的坚实基础上，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，目的是确定哪些反应对保护性疫苗诱导最重要，以及哪些序列最重要，以纳入有效的免疫原。具体地说，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)通过对血清转换前确定的受试者进行深度测序来确定应用于急性HIV-1分支C病毒感染的免疫选择压力的演变，以及对病毒适合性的影响，以及(3)确定在急性HIV-1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