Pathogenesis of Clade C HIV Infection

C 分支 HIV 感染的发病机制

• 批准号: 8282601
• 负责人: Bruce D Walker
• 金额: $ 60.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282601
• 关键词: Acute; African; Antigens; Antiviral Agents; Area; B-Lymphocytes; CD8B1 gene; Characteristics; Chronic; Chronic Phase; Containment; Data; Disease Outcome; Disease Progression; Employee Strikes; Epidemic; Epitopes; Equilibrium; Evolution; Foundations; Funding; Goals; Grant; HIV; HIV Infections; HIV vaccine; HIV-1; Heart; Human; Immune; Immune response; Immunogenetics; In Vitro; Incidence; Individual; Infection; Lead; Manuscripts; Mediating; Memory; Mutation; Pathogenesis; Pattern; Persons; Population; Relative (related person); Research; Sampling; Site; Specificity; Staging; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Tissues; Vaccines; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Work; arm; cohort; critical period; cytokine; design; fitness; immunogenicity; in vivo; neutralizing antibody; population based; pressure; prevent; response; success; vaccine candidate

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

描述（由申请人提供）：经过将近3年的集中研究工作，有效的HIV疫苗仍然是一个难以捉摸的目标。尽管在产生疫苗诱导的T和B细胞反应方面取得了成功，但目前没有候选铅疫苗。迄今为止，有证据表明，基于广泛的人群疗效将需要T和B细胞反应，以防止最初的局部组织感染完全确定，并应调节病毒血症。为此，定义HIV特异性CD8 T细胞反应的效应子臂仍然至关重要，这毫无疑问是一种与病毒控制最密切相关的免疫参数。此外，由于将在新感染的高发病率领域进行疫苗研究，因此对于这些人群中的循环病毒物种以及感染后产生的免疫反应至关重要。在这笔赠款的过去资金期间，我们在建立急性和慢性HIV感染的人群中取得了重大进展，在非洲流行病的核心工作，并使用这些人开始定义T细胞反应的免疫原性，特异性，免疫原料和功能。我们的数据毫无疑问，所有HIV特异性CD8 T细胞反应有助于控制体外和体内病毒血症。此外，在急性感染中，在病毒血症最快下降的过程中，尽管在感染菌株中存在同源表位，但仅针对慢性感染的表位是针对慢性感染的，而其中只有一小部分似乎施加了免疫选择压力。这种竞争性更新的目的是建立在该赠款的初始资金期间成立的企业基础上，以对急性感染的关键感染期间对抗HIV的有效和无效的免疫反应进行全面分析，目的是定义那些对使用保护性疫苗诱导的最重要的反应，以及这些对有效免疫原融合到有效免疫原中最重要的序列。具体而言，我们提出（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）定义了在急性HIV-1进化核C病毒感染中通过深度测序对急性及其在血清的影响（3）的作用（3）的影响（3）的影响（3）的影响（3）定义的（3）定义了（3），并定义了（3）的作用（3）。急性进化枝C病毒感染中的T细胞反应