Cellular Immune Response to non-B Clade HIV Infection

描述（由申请方提供）：已经提出了进化枝B HIV-1和其他亚型的发病机制之间的相似性，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起关键作用，并且仍然是疫苗开发中的重要焦点。在世界上非进化枝B感染占主导地位的地区，表征这些病毒的免疫发病机制是至关重要的，因为尚不清楚它们是否可能引起不同的免疫应答，从而需要不同的预防和治疗方法。另一个地理问题是HLA等位基因在不同种族人群中的频率差异。抗逆转录病毒治疗（ARV）在美国和欧洲（其中分支B占主导地位）的结构性治疗中断（STI）提供了一个独特的机会，以评估细胞免疫反应在控制病毒血症的作用。这些研究为研究体内细胞免疫控制病毒复制提供了模型。直到最近，这种研究在许多资源贫乏的环境中还不可行，特别是在非洲，非B分支占主导地位。乌干达最近采用了抗逆转录病毒疗法，目前正在坎帕拉的联合临床研究中心进行两项临床研究，分别评价抗逆转录病毒和STi。这些研究为我们提供了一个独特的机会，以评估非B分支HIV-1感染和各种ARV方案的免疫应答。我们推测，抗病毒细胞免疫的决定因素可能与不同地理区域的不同分支不同。该提案的目标是进一步剖析非B分支HIV感染的因素，对免疫治疗和疫苗开发具有潜在意义。具体而言，我们建议：1）在宿主HLA类等位基因的背景下，确定T细胞对乌干达进化枝A和D病毒株的应答; 2）使用CD 8 + 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STI的乌干达人队列的细胞免疫应答，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.