Viral evolution in peripheral macrophages and brain during progression to AIDS

项目摘要： 据估计，50%的HIV+患者仍表现出中枢神经系统（CNS）病毒感染，其中30%的患者 患者进展为某种形式的HIV相关神经认知障碍（HAND），尽管联合抗 逆转录病毒疗法（cART）。在先前资助的NIH R 01（NS 063897 - 01 A2）项目中- 外周巨噬细胞和大脑在进展到艾滋病-我们使用SIV感染的猕猴模型， neuroAIDS显示，在未治疗的动物中，SIV可以多次进入CNS，早在10天后 感染，在整个疾病过程中。感染大脑的SIV亚群在进化上是相关的 感染外周组织如骨髓和肺中的髓样细胞的病毒株， 在早期感染的脑膜和脉络丛中，以及在血管周围间隙和SIV相关的 脑炎（SIVE）病变晚期感染。此外，我们发现证据表明，正在进行的进化，在外围 在感染后期，组织导致病毒谱系的出现，适应进入CNS并在CNS中复制 可能与SIVE发作有关的微环境。然而，cART对时间和模式的影响 病毒进入中枢神经系统还有待分析，这对于解释为什么HAND甚至在中枢神经系统中也存在至关重要。 病毒抑制的患者。目前关于竞争性续约的建议旨在延长 通过表征导致CNS感染的病毒的进化行为， cART存在下CNS特异性病毒和宿主基因表达的后续调节。我们寻求 特别是评价外周血单核细胞和富含单核细胞/巨噬细胞的组织作为潜在来源 cART期间CNS病毒的感染，以及持续存在的CNS（和外周组织）病毒对病毒感染的贡献。 治疗中断后反弹。提出了两个具体目标：具体目标1 -确定 早期cART对病毒进化模式以及病毒和宿主基因表达模式的影响， SIV感染恒河猴中枢神经系统的病毒进入和复制;特异性目标2 -确定相对 SIV感染的巨噬细胞亚群在中枢神经系统和外周组织中对低水平病毒血症的贡献 cART中断后cART和病毒反弹。病毒进化模式的阐明和 特定感染组织/细胞群对CNS感染的贡献，在存在或随后 缺乏cART，将非常有益于未来的研究，旨在调整目前的治疗策略 对预防和消除neuroAIDS，并形成中枢神经系统水库，这是必要的 这是开发艾滋病治愈方法的一步。

Project Summary: An estimated 50% of HIV+ patients still exhibits central nervous system (CNS) viral infection, with 30% of patients progressing to some form of HIV-associated neurocognitive disorder (HAND) despite combined anti- retroviral therapy (cART). In the previously funded NIH R01 (NS063897-01A2) project – Viral evolution in peripheral macrophages and brain during progression to AIDS – we used the SIV-infected macaque model of neuroAIDS to show that in untreated animals SIV can enter the CNS multiple times, as early as 10 days post infection, throughout the course of the disease. SIV subpopulations infecting the brain are evolutionarily related to viral strains infecting myeloid cells in peripheral tissues, such as bone marrow and lung, which accumulate in the meninges and choroid plexus in early infection, and in the perivascular space and SIV-associated encephalitis (SIVE) lesions in late infection. Moreover, we found evidence that ongoing evolution in peripheral tissues leads, late in infection, to the emergence of viral lineages adapted to enter and replicate in the CNS microenvironment that may be linked to SIVE onset. However, the impact of cART on the timing and mode of entry of virus into the CNS has yet to be analyzed, which is crucial to explain why HAND is present even in virally suppressed patients. The present proposal for a competitive renewal seeks to extend the studies of the original project by characterizing the evolutionary behavior of the virus leading up to CNS infection and subsequent regulation of CNS-specific viral and host genes expression in the presence of cART. We seek to evaluate, in particular, peripheral blood monocytes and monocyte/macrophage rich tissues as potential source of CNS virus during cART, and the contribution of persisting CNS (and peripheral tissues) virus to viral rebound after therapy interruption. Two specific aims are proposed: Specific Aim 1 – Determine the impact of early cART on viral evolutionary patterns, as well as viral and host gene expression patterns, associated with viral entry and replication in the CNS of SIV-infected rhesus macaques; Specific Aim 2 – Determine relative contribution of SIV-infected macrophage subsets in the CNS and peripheral tissues to low-level viremia during cART and viral rebound following cART interruption. The elucidation of viral evolutionary patterns and the contribution of specific infected tissues/cell populations to CNS infection, in the presence or subsequent absence of cART, would be highly beneficial to future studies designed to adjust current therapeutic strategies toward the prevention and elimination of neuroAIDS, and formation of the CNS reservoir, which is a necessary step for the development of an HIV cure.