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

摘要 HIV-1感染是疫苗开发的一个世界性问题。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。 大部分早期的免疫发病机制研究是在欧洲和美洲进行的。 然而，撒哈拉以南非洲是HIV-1流行病的中心，宿主和病毒遗传学各不相同 地理区域之间的差异。非洲人群的MHC等位基因与那些 在西方，有一种病毒序列的多样性，这是不同于进化枝B株 统治着欧洲和美洲此外，撒哈拉以南非洲的环境 不同的;特别是有许多寄生虫感染是免疫调节，并可能影响 宿主对HIV-1感染和疫苗反应。 由于细胞免疫在HIV-1发病机制中起着重要的保护作用， 已经大量关注产生抗病毒CD 8 + T淋巴细胞（CTL）应答以减弱感染（如果 不提供全面保护）。然而，默克公司最近决定放弃其二期临床试验， （STEP）由于缺乏有效性，强调了更好地了解 HIV-1感染的免疫发病机制及影响CTL抗病毒效果的因素。 乌干达是一个HIV-1迅速蔓延的国家，但它的反应却非同寻常 to the AIDS艾滋病epidemic流行.这是非洲第一个测试HIV-1疫苗的国家， 在向受影响人口引入抗逆转录病毒（ARV）方案方面发挥领导作用。在前期资金 在R 01期间，我们利用了这个国家对HIV-1研究的奉献精神， 建立了研究免疫发病机制的基础设施。乌干达提供了独特的机会， 解决撒哈拉以南非洲特有的相关问题， 立即。 该更新项目将探讨与疫苗和免疫学相关的问题 在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一个平台。我们将 探讨宿主和病毒遗传学的影响，以及寄生蠕虫的免疫调节作用 HIV-1感染的免疫发病机制。我们提出的三个目标是： 1)为了确定HIV-1特异性CTL在乌干达基因组中的靶向性和跨进化枝抗病毒活性， contexts. 2)为了检测乌干达遗传性HIV-1感染者中CTL表位变异和Nef介导的HIV-1免疫逃避， contexts. 3)为了评估地方性合并感染是否可以调节乌干达的HIV-1免疫发病机制， 使用曼氏血吸虫作为感染模型。

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.