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

描述（由申请人提供）：越来越多的人接受非人灵长类动物（NHP）模型和研究在HIV-1基础疫苗发现中发挥关键作用，可能提供有关疫苗概念免疫原性和有效性的有价值信息，将候选疫苗推进人体临床试验。由于单个HIV-1疾病的NHP模型不太可能满足所有临床前需求，因此需要努力改进或优化现有模型，以便有效利用它们，并开发新的实验工具以拓宽NHP模型的应用。考虑到这一点，我们最近发现，静脉内（IV）或直肠内（IR）接种印度恒河猴（RM）与晚期R5 SHIVSF 162 P3 N分离概括了人类HIV-1感染的关键致病特征，包括急性CD 4 + T细胞在肠道中的损耗，不受控制的复制，并进展为艾滋病与辅受体偏好的开关。在SHIVSF 162 P3 N IV和IR感染的猕猴中观察到的高设定点病毒血症和致病性的一致性，以及SHIVSF 162 P3 N的包膜显示出传播的创始人HIV-1 R5病毒的典型抗原特性的发现，使我们假设该病毒将高度相关并可用于促进刺激免疫系统的两个效应臂的HIV-1候选疫苗的发现，允许对基于T和B细胞的疫苗概念进行比较以及协同研究。为了进一步优化这种新病毒，我们将评估剂量（单次高vs.重复低）、接种途径（阴道内vs.直肠内）和猕猴来源（印度vs.中国）对R5 SHIVSF 162 P3 N病理生理学的影响，目的是确定其用于疫苗研究的广泛性（目的1）。还将尝试产生致病性R5 SHIVSF 162 P3 N分子克隆，以研究接种疫苗的猕猴中病毒逃逸和突破的机制，从而可能提供对保护的免疫学相关性的见解（目的2）。最后，为了解决病毒多样性问题并更接近地模拟人类中HIV-1暴露的情况，提出了一种新方法，其中中和敏感亚型C R5 Env的包膜将用于构建用于RM中连续传代的SHIV，目的是产生致病性非亚型B R5 SHIV作为NHP中的攻击病毒（目的3）。这些研究优化/完善了现有的R5 SHIVSF 162 P3 N模型，并开发了其他实验工具，如致病性，CCR 5-使用携带遗传多样性包膜的SHIV作为挑战病毒储备，应提供更广泛的生物学相关模型和挑战病毒，用于HIV-1疫苗的临床前评价，提高NHP研究的预测价值。制定疫苗等预防战略仍然是控制艾滋病流行病的主要优先事项。在非人灵长类动物（NHP）中的研究预计将在HIV-1基础疫苗的发现中发挥关键作用，提供关于载体和免疫策略的比较免疫原性和有效性的有价值的信息，将有希望的候选疫苗推进人体临床试验。建立一套具有生物学相关性和广泛特征的模型的研究工作将扩大NHP研究的应用范围，提高NHP研究的预测价值。

DESCRIPTION (provided by applicant): There is growing acceptance of nonhuman primate (NHP) models and studies as playing a critical part in HIV-1 basic vaccine discovery, potentially providing valuable information on the immunogenicity and efficacy of vaccine concepts, advancing candidate vaccines into human clinical trials. As it is unlikely that a single NHP model for HIV-1 disease will satisfy all the preclinical needs, efforts are needed to improve or optimize existing models so that they can be utilized effectively, as well as develop new experimental tools to broaden the applications of NHP models. With this in mind, we recently find that intravenous (IV) or intrarectal (IR) inoculation of Indian rhesus macaques (RMs) with the late R5 SHIVSF162P3N isolate recapitulates key pathogenic features of HIV-1 infection in humans including acute CD4+ T cell depletion in the gut, uncontrolled replication, and progression to AIDS with switch in coreceptor preference. The consistency of high setpoint viremia and pathogenicity seen in SHIVSF162P3N IV and IR infected macaques, and the finding that the envelope of SHIVSF162P3N displays antigenic properties typical of the transmitted founder HIV-1 R5 viruses lead us to hypothesize that this virus will be highly relevant and useful for advancing the discovery of HIV-1 candidate vaccines that stimulate both effector arms of the immune system, allowing for comparative as well as synergistic studies of T and B cell-based vaccine concepts. To further optimize this new virus, we will assess the impact of dose (single high vs. repeat low), route of inoculation (intravaginal vs. intrarectal), and macaque origin (Indian vs. Chinese) on R5 SHIVSF162P3N pathophysiology, with the goal of establishing the breadth of its utility for vaccine research (Aim 1). Attempts will also be made to generate a pathogenic R5 SHIVSF162P3N molecular clone to study the mechanisms of viral escape and breakthrough in vaccinated macaques, potentially providing insights on the immunological correlates of protection (Aim 2). Lastly, to address the issue of viral diversity and more closely mimic the situations of HIV-1 exposures in humans, a novel approach is proposed whereby the envelope of neutralization-sensitive subtype C R5 Envs will be used in the construction of SHIVs for serial passaging in RMs, the objective being the generation of pathogenic non-subtype B R5 SHIVs as challenge viruses in NHPs (Aim 3). These studies to optimize/refine existing R5 SHIVSF162P3N models and develop additional experimental tools such as pathogenic, CCR5-using SHIVs that carry genetically-diverse envelopes as challenge virus stocks should provide a wider range of biologically relevant models and challenge viruses for preclinical evaluation of HIV-1 vaccines, improving the predictive value of NHP studies. The development of prevention strategies such as vaccines remains a major priority for the control of the AIDS pandemic. Studies in nonhuman primates (NHP) are anticipated to play a critical part in HIV-1 basic vaccine discovery, providing valuable information on the comparative immunogenicity and efficacy of vectors and immunization strategies, advancing promising candidate vaccines into human clinical trials. Research efforts to establish a set of biologically relevant and extensively-characterized models should broaden the applications, and improve the predictive value of NHP studies.