To study cellular immune response in non-B clade HIV infection

摘要 HIV-1感染是疫苗研发的世界性难题。超过2500万人被感染 在撒哈拉以南非洲，这一地理区域对疫苗开发构成了独特的挑战。 早期对免疫发病机制的大部分研究都是在欧洲和美洲进行的。 然而，撒哈拉以南非洲是艾滋病毒-1流行的震中，宿主和病毒基因各不相同 地理区域之间的差异显著。非洲人群的MHC等位基因与 并且有不同于B分支病毒株的多样性的病毒序列 主宰着欧洲和美洲。此外，撒哈拉以南非洲的环境 不同；特别是有许多寄生虫感染是免疫调节的，可能会影响 宿主对HIV-1感染和疫苗的反应。 由于细胞免疫在HIV-1发病机制中起着重要的保护作用，最近的疫苗努力 主要致力于产生抗病毒的CD8+T淋巴细胞(CTL)反应以减少感染(IF 不提供全面保护)。然而，默克公司最近决定放弃其第二阶段临床试验 (步骤)由于缺乏效力，强调了更好地了解 HIV-1感染的免疫发病机制及CTL抗病毒效果的影响因素 乌干达是艾滋病毒-1迅速传播的国家，但其应对措施非同寻常 爱滋病的流行。这是非洲第一个测试艾滋病毒-1疫苗的国家，乌干达已经采取了 在向受影响的人群推出抗逆转录病毒(ARV)计划方面处于领先地位。超过了之前的资金 在这次R01期间，我们利用了这个国家对艾滋病毒-1研究的奉献精神，以及 在那里建立了研究免疫致病机制的基础设施。乌干达提供了一个独特的机会 处理撒哈拉以南非洲特有的相关问题，在调查结果可应用的情况下 要立即行动。 这一更新项目将探讨与疫苗和免疫治疗相关的问题。 撒哈拉以南非洲的干预措施，利用我们在乌干达的研究业务作为平台。我们会 探讨宿主和病毒遗传学的影响以及并发蠕虫的免疫调节作用 关于HIV-1免疫发病机制的感染。我们建议的三个目标是： 1)确定乌干达基因中HIV-1特异性CTL的靶向性和交叉抗病毒活性 上下文。 2)检测乌干达基因中CTL表位变异和Nef介导的HIV-1免疫逃避 上下文。 3)评估地方性混合感染是否可能调节乌干达艾滋病毒-1的免疫致病作用， 以曼氏血吸虫作为模型感染。

ABSTRACTS HIV-1 infection is a worldwide problem for vaccine development. More than 25 million people are infected with in sub-Saharan Africa, a geographic area that poses unique challenges for vaccine development. The bulk of earlier studies of immunopathogenesis have been performed in Europe and the Americas. However, sub-Saharan Africa is the epicenter of the HIV-1 epidemic, and host and viral genetics vary significantly between geographic regions. The MHC alleles of African human populations vary from those of the West, and there is a diversity of viral sequences that are distinct from the Clade B strains dominating Europe and the Americas. Furthermore, the environment in sub-Saharan Africa is vastly different; in particular there are many parasitic infections that are immunomodulatory and likely affect the host response to HIV-1 infection and vaccines. Because cellular immunity plays an important protective role in HIV-1 pathogenesis, recent vaccine efforts have focused heavily on generating antiviral CD8+ T lymphocyte (CTL) responses to attenuate infection (if not provide full protection). However, the recent decision by Merck to abandon its Phase II clinical trial (STEP) due to lack of efficacy underscores the importance of better understanding mechanisms in the immunopathogenesis of HIV-1 infection and factors affecting the antiviral efficiency of CTL . Uganda is a country in which HIV-1 has spread rapidly, but which has been extraordinary in its response to the AIDS epidemic. This was the first country in Africa to test HIV-1 vaccines, and Uganda has taken leadership in introducing antiretroviral (ARV) programs to its affected population. Over the prior funding periods of this R01, we have capitalized on the dedication of this country to HIV-1 research, and established the infrastructure to study immunopathogenesis there. Uganda offers a unique opportunity to address relevant issues specific to sub-Saharan Africa, in a setting where applications of the findings may be immediate. This renewal project will pursue questions that are relevant for vaccine and immunotherapeutic interventions in sub-Saharan Africa, employing our research operation in Uganda as a platform. We will explore the influences of host and viral genetics, and immunomodulatory effects of concurrent helminth infections on HIV-1 immunopathogenesis. Our proposed three aims are: 1) To determine the targeting and cross-clade antiviral activity of HIV-1-specific CTL in Ugandan genetic contexts. 2) To examine CTL epitope variation and Nef-mediated HIV-1 immune evasion in Ugandan genetic contexts. 3) To evaluate whether endemic co-infections may modulate of HIV-1 immununopathogenesis in Uganda, using Schistosoma mansoni as a model infection.