Generation of Genotypically Diverse R5 SHIVs as Tools in HIV-1 Vaccine Research

描述（由申请人提供）：本R24申请的目标是生成一组可靠的致病性R5 SHIV，代表全球流行的HIV-1毒株，重点是助长HIV-1大流行的C亚型和CRF_AE。我们设想，这些新的SHIV概括了人类HIV的免疫发病机制，将作为有价值的资源，不仅作为临床前非人灵长类动物（NHP）研究中的挑战病毒，以确定疫苗诱导的免疫是否具有针对单一遗传亚型内以及亚型间多种变体的活性，而是为了提高我们对艾滋病毒引起的免疫缺陷的发病机制的认识，以推动治疗、预防和治愈方面的进展。拟议的项目利用了Cheng-Mayer博士在艾滋病SHIV模型和Blanchard博士在非人灵长类动物医学方面的互补专业知识，并建立在我们在HIV-1疫苗和发病机制研究中成功产生R5 SHIV的经验基础上。 在目标1中，我们将表征最近获得的晚期SHIVC分离株的粘膜传播能力，持久维持慢性病毒血症，并诱导疾病与巨细胞脑炎和辅助受体转换的发展一致。在目标2中，我们将构建另外三个表达来自传递者/创始者或早期感染亚型C和CRF_01AE病毒的Env的R5 SHIV分子克隆。我们将通过在印度恒河猴中进行四次快速连续传代来适应和提高它们的体内复制能力，印度恒河猴是艾滋病研究中最常用的猴种。将监测后期传代猕猴的疾病发展。在目标3中，我们将通过评估其粘膜传播性和诱导慢性病毒血症和免疫缺陷的能力，评价从C亚型和CRF_AE SHIV传代病猴中回收的群无细胞病毒作为攻毒病毒的适用性。 我们认为，这些资源的潜在影响是巨大的。资源应用程序包括：（1）在NHP中开发用于艾滋病疫苗研究的工具;（2）开发用于临床前暴露前预防（PrEP）、治疗和治愈研究的工具;（3）调查HIV-1亚型与免疫系统在急性和慢性感染期间的相互作用;（4）调查HIV-1亚型对艾滋病发病机制的影响。我们设想R5 SHIV和产生的模型将指导疫苗设计和开发，产生艾滋病发病机制的新假设和实验，以推进基础和转化发现研究，并促进HIV预防，治疗和治愈的临床前研究。

DESCRIPTION (provided by applicant): The goal of this R24 application is to generate a panel of reliable pathogenic R5 SHIVs representing globally circulating HIV-1 strains, with emphasis on subtype C and CRF_AE that are fueling the HIV-1 pandemic. We envision that these novel SHIVs which recapitulate the immunopathogenesis of HIV in humans will serve as valuable resources not only as challenge viruses in preclinical nonhuman primate (NHP) studies to determine if vaccine-induced immunity has activities against multiple variants within a single genetic subtype as well as across subtypes, but to improve our understanding on the pathogenesis of the HIV-induced immunodeficiency to advance progress towards treatment, prevention and cure. The proposed project leverages the complementary expertise of Dr. Cheng-Mayer in SHIV models of AIDS and of Dr. Blanchard in nonhuman primate medicine, and builds on our documented experience in generating successful R5 SHIVs in HIV-1 vaccine and pathogenesis studies. In aim 1, we will characterize a recently obtained late-stage SHIVC isolate for its ability to transmit mucosally, maintain chronic viremia durably and induce disease consistently with development of giant cell encephalitis and coreceptor switching. In aim 2, we will construct three additional R5 SHIV molecular clones expressing Envs from transmitter/founder or early infection subtype C and CRF_01AE viruses. We will adapt and improve their replicative capacity in vivo by performing four rapid serial passages in Indian rhesus macaques, the most commonly used monkey species for AIDS research. Development of disease in the late passage macaques will be monitored. In aim 3, we will evaluate the suitability of swarm cell-free viruses recovered from the subtype C and CRF_AE SHIV passage macaques with disease as challenge viruses by assessing their mucosal transmissibility and ability to induce chronic viremia and immunodeficiency. We believe the potential impact of the resources is substantial. Resource applications include: (1) development of tools for AIDS vaccine research in NHPs; (2) development of tools for preclinical pre-exposure prophylaxis (PrEP), therapeutic and cure studies; (3) investigation of the interaction between HIV-1 subtype and the immune system during acute and chronic infection; (4) investigation of the impact of HIV-1 subtype on AIDS pathogenesis. We envision the R5 SHIVs and models generated will guide vaccine design and development, generate new hypotheses and experiments in AIDS pathogenesis to advance basic and translational discovery research, and facilitate preclinical research in HIV prevention, therapeutics and cure.