Viral evolution in peripheral macrophages and brain during progression to AIDS

项目总结： 据估计，50%的艾滋病毒+患者仍表现出中枢神经系统(CNS)病毒感染，其中30% 尽管联合抗艾滋病药物，患者仍进展为某种形式的HIV相关神经认知障碍(HAND) 逆转录病毒疗法(CART)。在先前资助的NIH R01(NS063897-01A2)项目中-病毒在 外周巨噬细胞和脑在发展为艾滋病-我们使用SIV感染的猕猴模型 神经艾滋病显示，在未经治疗的动物中，SIV可以多次进入中枢神经系统，最早可在10天后 感染，贯穿于疾病的整个过程。感染大脑的SIV亚群与进化相关 感染周围组织中的髓样细胞的病毒株，如骨髓和肺，这些病毒株积累 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 脑炎(SIVE)病变以晚期感染为主。此外，我们发现有证据表明，外围设备正在进行的进化 在感染后期，组织导致适应进入并在中枢神经系统复制的病毒谱系的出现 微环境可能与SIVE的发病有关。然而，CART对中国经济发展的时机和模式的影响 病毒进入中枢神经系统的情况还有待分析，这对于解释为什么即使在 病毒抑制的病人。目前关于竞争性续签的建议旨在扩大对 最初的项目通过表征导致中枢神经系统感染的病毒的进化行为和 在CART存在的情况下，随后调节CNS特异性病毒和宿主基因的表达。我们寻求 特别是评估外周血单核细胞和富含单核/巨噬细胞的组织作为潜在来源 CART期间CNS病毒的变化，以及CNS(和外周组织)持续病毒对病毒的贡献 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病毒进化模式，以及病毒和宿主基因表达模式，与 感染SIV的恒河猴中枢神经系统中病毒的进入和复制；特定目标2-确定亲属 中枢神经系统和周围组织中SIV感染的巨噬细胞亚群在低水平病毒血症中的作用 购物车中断后，购物车和病毒反弹。病毒进化模式的阐明和病毒的 特定感染组织/细胞群体在中枢神经系统感染中的作用 CART的缺失，将对未来旨在调整当前治疗策略的研究非常有益 对于预防和消除神经艾滋病，并形成中枢神经系统的储备库，这是必要的 为开发艾滋病毒治疗药物迈出了一步。

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.