Cellular Immune Response to non-B Clade HIV Infection

描述(申请人提供)：已经提出了B分支HIV-1与其他亚型之间的相似发病机制，但尚未得到证实，非B亚型HIV-1感染的免疫发病机制仍未得到充分研究。HIV-1感染中的细胞免疫被认为在病毒控制中发挥着关键作用，并且仍然是疫苗开发中的一个重要焦点，在世界上一个非B分支感染占主导地位的地区，确定这些病毒的免疫发病机制至关重要，因为尚不清楚它们是否会引起不同的免疫反应，从而需要不同的预防和治疗方法。另一个地理问题是不同种族人群中人类白细胞抗原等位基因频率的差异。美国和欧洲(以B分支为主)的抗逆转录病毒治疗(ARV)的结构化治疗中断(STI)为评估细胞免疫反应在控制病毒血症中的作用提供了一个独特的机会。这些研究为研究体内病毒复制的细胞免疫调控提供了模型。直到最近，这类研究在许多资源贫乏的地区都是不可行的，在那里非B类分支占主导地位，特别是在非洲。乌干达最近采用了抗逆转录病毒疗法，坎帕拉联合临床研究中心目前正在进行两项分别评估抗逆转录病毒和性传播感染的临床研究。这些研究为我们提供了一个独特的机会来评估在非B分支HIV-1感染和各种ARV方案下的免疫反应。我们假设，抗病毒细胞免疫的决定因素可能因不同地理区域的不同分支而不同。这项提案的目标是进一步剖析非B类HIV感染的因素，对免疫疗法和疫苗开发具有潜在的影响。具体地说，我们建议：1)在宿主HLA类等位基因的背景下，确定乌干达A和D分支病毒株的T细胞反应；2)使用CD8+T细胞克隆进行抗病毒功能的机制研究；3)分析接受持续高效抗逆转录病毒治疗(HAART)和性传播感染的乌干达个体的细胞免疫反应，并研究这一人群中免疫控制的相关性。

DESCRIPTION (provided by applicant): Analogies between the pathogenesis of clade B HIV-1 and other subtypes have been proposed but not proven, and the immunopathogenesis in non-B subtype HIV-1 infection remains inadequately explored. Cellular immunity in HIV-1 infection is believed to play a key role in viral control, and remains an important focus in vaccine development, in a region of the world where non-clade B infections predominate, it is crucial to characterize the immunopathogenesis of these viruses, because it is unclear whether they may elicit different immune responses and thus require different preventive and therapeutic approaches. Another geographic issue is the differential frequency of HLA alleles in different ethnic populations. Structured treatment interruptions (STI) of antiretroviral therapy (ARV) in the U.S. and Europe (where clade B predominates) have provided a unique opportunity to evaluate the role of cellular immune responses in the control of viremia. These studies have provided a model for the study of cellular immune control of viral replication in vivo. Until recently, such studies have not been feasible in many resource-poor settings where non-B clades predominate, particularly in Africa. Antiretroviral therapy has recently been introduced to Uganda, where two clinical studies evaluating ARV and STi, respectively, are currently ongoing at the Joint Clinical Research Centre in Kampala. These studies provide us a unique opportunity to evaluate the immune response in the setting of non-B clade HIV-1 infection and various ARV regimens. We hypothesize that the determinants antiviral cellular immunity could differ with the varying clades in distinct geographic regions. The goals of this proposal are to further dissect factors in non-B clade HIV infection, with potential implications in immunotherapeutics and vaccine development. Specifically, we propose: 1) To determine the T cell responses to clade A, and D viral strains in Uganda, in the context of the host HLA class alleles; 2) To perform mechanistic studies of antiviral function using CD8+ T cell clones; 3) To analyze the cellular immune responses in a cohort of Ugandan individuals Ireceiving continuous highly active antiretroviral therapy (HAART) and STI, and study the correlates of immune control in this population.