Cellular Immune Response to non-B Clade HIV Infection

描述（由申请人提供）：已提出B支HIV-1的发病机制与其他亚型之间的相似性，但尚未得到证实，非B亚型HIV-1感染的免疫发病机制仍未充分探索。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的一个重要重点，在世界上非B支感染占主导地位的地区，确定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反应，因此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。在美国和欧洲（以B支为主），抗逆转录病毒治疗（ARV）的结构化治疗中断（STI）提供了一个独特的机会来评估细胞免疫反应在控制病毒血症中的作用。这些研究为细胞免疫控制病毒在体内复制的研究提供了一个模型。直到最近，在许多资源贫乏的环境中，特别是在非洲，这种研究还不可行，这些环境中非b支占主导地位。抗逆转录病毒疗法最近被引入乌干达，坎帕拉的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非b支HIV-1感染和各种抗逆转录病毒治疗方案的免疫反应。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进化枝而异。这项建议的目标是进一步剖析非b支HIV感染的因素，对免疫治疗和疫苗开发具有潜在的意义。具体来说，我们建议：1)在宿主HLA类等位基因的背景下，确定乌干达的T细胞对A和D支病毒株的反应；2)利用CD8+ T细胞克隆进行抗病毒功能的机制研究；3)分析乌干达接受持续高效抗逆转录病毒治疗（HAART）和性传播感染人群的细胞免疫应答，研究该人群免疫控制的相关因素。

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.