R5 SHIV/Macaque Models for the Evaluation of T and B Cell-Based HIV-1 Vaccines

越来越多的数据表明，中和和非中和结合抗体与 防止艾滋病毒感染。因此，诱导这些抗体现在是HIV-1的高度优先事项 疫苗开发和非人灵长类动物（NHP）攻击模型在临床前研究中发挥着关键作用。 评估疫苗诱导反应的有效性和广度。至少有九种不同的基因 亚型和越来越多的M组HIV-1的循环重组形式占大多数， 全球新发感染病例中，C亚型病毒在感染负担最重的国家占主导地位。 感染因此，需要代表全球传播的HIV-1毒株的可靠的NHP攻毒储备， 确定疫苗诱导的免疫是否对单一遗传亚型内的多种变体具有活性 以及跨亚型。了解亚型在发病机制和传播方面差异的基础 在设计有效的预防战略方面也很重要。在当前的融资周期中，我们充分 表征了用于疫苗研究的致病性亚型B R5 SHIVSF 162 P3 N感染模型，并成功地 构建了该分离株的分子克隆，其诱导肠道中的急性CD 4 + T细胞耗竭，进展为 AIDS伴辅助受体转换，与外周CD 4下降和V3环序列改变一致。更 重要的是，我们产生了一系列谱系相关的粘膜传播亚型C R5 SHIV， 也能够诱导AIDS，具有神经病理学发展和终末辅助受体转换 疾病在此竞争性更新应用程序中提出的实验旨在扩展这些成功 通过构建亚型C R5 SHIV分子克隆以及另外的非亚型B SHIV， 概括人类HIV-1作为攻击病毒的免疫发病机制，以提高效用， SHIV/猕猴模型的预测价值。我们还将使用致病亚型B和CR 5 SHIV 作为解决HIV-1复制、免疫学和疾病中是否存在亚型差异的工具。 三个假设将在实验中进行测试，具体目标如下： 目的1：构建具有与SHIV感染和病理学类似的感染动力学和病理学的C亚型R5 SHIV分子克隆。 人类感染我们假设这些分子克隆对解剖研究很重要， 影响疾病结果和疫苗逃逸的env的进化变化。 目的2：使用sCD 4-敏感性细胞因子产生和表征额外的致病性非亚型B R5 SHIV transmitted/founder Envs.我们假设使用sCD 4敏感性Env有效结合CD 4， 提供了更好的成功产生高传染性和致病性SHIV的机会。 目的3：比较B和CR 5亚型SHIV感染RM的免疫发病机制.我们认为， 这些研究可能导致对影响HIV-1亚型传播的生物学和/或免疫学因素的识别 和疾病

Mounting data suggests that both neutralizing and non-neutralizing binding antibodies are associated with protection against HIV infection. Induction of these antibodies therefore is now a high priority for HIV-1 vaccine development, and nonhuman primate (NHP) challenge models play a critical role in the pre-clinical evaluation of the effectiveness and breadth of vaccine-induced responses. At least nine different genetic subtypes and a growing number of circulating recombinant forms of group M HIV-1 account for the majority of new infections worldwide, with subtype C viruses predominating in countries that carry the heaviest burden of infection. Reliable NHP challenge stocks representing globally circulating HIV-1 strains therefore are needed to determine if vaccine-induced immunity has activities against multiple variants within a single genetic subtype as well as across subtypes. Understanding the basis for subtype differences in pathogenesis and transmission will also be important in the design of effective prevention strategies. In the current funding cycle, we fully characterized the pathogenic subtype B R5 SHIVSF162P3N infection model for vaccine studies, and successfully constructed molecular clones of this isolate that induce acute CD4+ T cell depletion in the gut, progression to AIDS with coreceptor switch coincident with peripheral CD4 decline and V3 loop sequence change. More importantly, we generated a series of lineage-related, mucosally transmissible subtype C R5 SHIVs that are also capable of AIDS induction, with neuropathological development and coreceptor switching at terminal disease. The experiments proposed in this competitive renewal application aim to expand on these successes by constructing subtype C R5 SHIV molecular clones as well as additional non-subtype B SHIVs that recapitulate the immunopathogenesis of HIV-1 in humans as challenge viruses to improve the utility and predictive value of the SHIV/macaque models. We will also use the pathogenic subtype B and C R5 SHIVs generated as tools to address if there are subtype differences in HIV-1 replication, immunology and disease. Three hypotheses will be tested in experiments with the following specific aims: Aim 1: Construct subtype C R5 SHIV molecular clones with dynamics of infection and pathologies akin to the human infection. We hypothesize that these molecular clones will be important for studies aimed at dissecting the evolutionary changes in env that influence disease outcomes and vaccine escape. Aim 2: Generate and characterize additional pathogenic non-subtype B R5 SHIVs using sCD4-sensitive transmitted/founder Envs. We hypothesize that the use of sCD4 sensitive Envs that bind CD4 efficiently provides a better chance of success in generating highly infectious and pathogenic SHIVs. Aim 3: Compare immunopathogenesis of subtype B and C R5 SHIV infection in RMs. We posit that such studies may lead to the identification of biologic and/or immunologic factors that impact HIV-1 subtype spread and disease.