Intra-Host Phylogeography and Population Dynamics of SIV in the Rhesus Macaque Model of NeuroAIDS

 描述（由申请人提供）：尽管引入了高效抗逆转录病毒治疗（HAART），但HIV-1感染患者中HIV相关神经认知障碍（HAND）的患病率有所增加。目前，没有有效的治疗HAND;因此，更好地了解在疾病发作和进展期间驱动神经毒力菌株出现的病毒进化因素对于开发神经AIDS的机制模型和改进药物设计策略至关重要。目前的建议的目的是确定和表征的时空动态的病毒进化的外周和中枢神经系统（CNS）的组织和细胞群体与神经发病机制的发病和进展在两个不同的恒河猴模型neuroAIDS。用遗传特征的病毒群感染总共18只猕猴，随时间推移收集外周血和组织样品，并用于扩增病毒gp 120基因组RNA。高分辨率的空间地理分析将揭示与脑缺血发作相关的宿主内病毒播种的空间和时间方面。 一种神经致病性感染，由于与人体组织取样相关的伦理问题，尚未被表征。具体目标1将通过纵向PBMC/组织采样和有和无CD 8+淋巴细胞耗竭的猕猴脑活检，研究感染过程中血浆中无细胞病毒和淋巴组织和外周血单核细胞（PBMC）中细胞相关病毒向CNS的迁移（基因流）。具体目标2将随着时间的推移测量脑炎相关脑损伤的生物标志物，以研究在具体目标1中观察到的病毒进化和群体动态与疾病发作和进展之间的联系。最终，我们将能够识别大脑感染的时空模式和导致 嗜神经性和神经毒性种群的出现，可用于预测和监测疾病进展。同样重要的是，这些发现在开发靶向与神经发病机制相关的病毒和/或感染的免疫细胞群体的药物中的潜在利用。总的来说，我们将进行最全面的分析纵向SIV序列从各种组织的日期。与这个项目相关的主要研究者，Marco Salemi博士，在系统发育分析方面有着丰富的经验，并致力于培养一个资源丰富的环境，这对这个项目的成功至关重要，也是我的前研究员。 博士生涯此外，我们还组建了一个独特且合格的跨学科咨询委员会，以协助监督和推进本研究。

 DESCRIPTION (provided by applicant): Despite the introduction of highly active antiretroviral treatment (HAART), the prevalence of HIV-associated neurocognitive disorders (HAND) among HIV-1-infected patients has increased. Currently, there is no effective therapy for HAND; therefore, a better understanding of the viral evolutionary factors driving the emergence of neurovirulent strains during disease onset and progression is of pivotal importance for developing a mechanistic model of neuroAIDS and improvement of drug design strategies. The objectives of the current proposal are to identify and characterize spatiotemporal dynamics of viral evolution among peripheral and central nervous system (CNS) tissues and cell populations associated with the onset and progression of neuropathogenesis in two distinct rhesus macaque models of neuroAIDS. Eighteen total macaques were infected with a genetically characterized viral swarm, from which peripheral blood and tissue samples were collected over time and used for amplification of viral gp120 genomic RNA. High-resolution phylogeographic analyses will reveal spatial and temporal aspects of intra-host viral seeding of the brain linked to the onset of a neuropathogenic infection that have not yet been characterized because of ethical issues associated with tissue sampling in humans. Specific Aim 1 will investigate the migration (gene flow) of cell-free virus from plasma and cell-associated virus from lymphoid tissues and peripheral blood mononuclear cells (PBMCs) to the CNS during the course of infection via longitudinal PBMC/tissue sampling and brain biopsies of macaques with and without CD8+ lymphocyte depletion. Specific Aim 2 will measure biomarkers of encephalitis-associated brain injury over time in order to investigate the link between viral evolutionary and population dynamics observed in Specific Aim 1 and disease onset and progression. Ultimately, we will be able to identify the spatiotemporal patterns of brain infection and evolutionary signatures leading to the emergence of neurotropic and neurovirulent populations that could be used to predict and monitor disease progression. Equally important is the potential utilization of these findings in th development of drugs that target viral and/or infected immune cell populations associated with neuropathogenesis. Overall, we will undertake the most comprehensive analysis of longitudinal SIV sequences from a variety of tissues to date. The principle investigator associated with this project, Dr. Marco Salemi, has significant experience in phylogenetic analysis and has worked to cultivate a resource-rich environment critical for the success of this project as well as my pre doctoral career. In addition, we have assembled a unique and qualified interdisciplinary advisory committee to assist in oversight and progression of this study.