Towards Suppression and Elimination of HIV in the CNS

项目摘要/摘要 尽管联合抗逆转录病毒疗法(CART)在减少外周感染方面取得了成功， HIV-1可以在中枢神经系统(CNS)建立感染，导致 与HIV-1相关神经认知相关的认知、行为和运动缺陷 精神障碍(手)。一旦被感染，中枢神经系统就像一个难以治疗和 铲除。单核巨噬细胞(MP，如血管周围巨噬细胞和小胶质细胞) 免疫特权中枢神经系统中的重要储蓄者。拟议的研究旨在 应对中枢神经系统艾滋病毒感染的独特动态，探索新的治疗策略 以MP为靶点，确保通过血脑屏障(BBB)可行地传递以消除艾滋病毒 蓄水消炎。HIV诱导MP中的激活和病毒复制是相关的 靶点是我们正在进行的通过多种药理学方法进行的新方法的重点 探员们。这些方法包括：1)MP特异性核糖核苷的设计和开发 链终止物(RNCT)及其磷酸前体药物，以及2)NADPH氧化酶(NOX)抑制剂 跨越血脑屏障和靶MP，以及3)JAK抑制剂，阻断/中断 MP，能消炎消炎。选定的治疗药物将在体外进行分析 抗病毒效力，并评估生物化学、毒理学和细胞药理学参数。 我们最近发现了低或亚纳摩尔的MP特异性HIV抑制剂，具有高的 治疗指数。这些药物将在体内进行评估，以评估中枢神经系统的药理学和反应 (包括行为和病理)使用两种不同的逆转录病毒CNS动物模型进行治疗 我们以前已经建立了包括脑内注射HIV-1的SCID小鼠模型 感染MP和SIVmac239感染猕猴模型。这些研究的结果将 确定新的辅助治疗策略，与当前的CART一起提供 改进了对MP的靶向治疗。最终目标是抑制病毒，消灭这些艾滋病毒-- 1中南地区的水库，应改进治疗措施以降低发病风险(S) 手。

PROJECT SUMMARY/ ABSTRACT Despite the success of combined antiretroviral therapy (cART) to diminish peripheral infection, HIV-1 can establish an infection in the central nervous system (CNS), resulting in the development of cognitive, behavioral, and motor deficits associated with HIV-1 associated neurocognitive disorders (HAND). Once infected, the CNS acts as a viral reservoir that is difficult to treat and eradicate. Mononuclear phagocytes (MP, e.g., perivascular macrophages and microglia) are important reservoirs in the immune-privileged CNS. The proposed studies are designed to address the unique dynamics of HIV infection in CNS and explore novel therapeutic strategies that target MP, ensure viable delivery across the blood-brain barrier (BBB) to eliminate the HIV reservoir and reduce inflammation. HIV-induced activation and viral replication in MP are relevant targets that that are the focus of our ongoing novel approaches through multiple pharmacological agents. These approaches include design and development of: 1) MP-specific ribonucleoside chain terminators (rNCTs) and their phosphate prodrugs, and 2) NADPH oxidase (NOX) inhibitors that cross the BBB and target MP, and 3) JAK inhibitors that block/interrupt the activation state of MP and can reduce inflammation. Selected therapeutic agents will be analyzed for their in vitro antiviral potency, and to assess biochemistry, toxicology, and cellular pharmacology parameters. We have recently identified low or sub-nanomolar MP-specific HIV inhibitors with a high therapeutic index. These will be evaluated in vivo to assess CNS pharmacology and response (including behavior and pathology) to treatment using two distinct retrovirus CNS animal models we have previously established including SCID mouse model intracranially injected with HIV-1 infected MP, and macaque model infected with SIVmac239. Results from these studies will identify new adjunctive therapeutic strategies which together with current cART should provide improved targeted therapy to MP. The ultimate goal is to suppress virus and eliminate these HIV- 1 reservoirs in the CNS that should lead to improved treatments to reduce risk(s) of developing HAND.