Towards Suppression and Elimination of HIV in the CNS

项目概要/摘要 尽管联合抗逆转录病毒疗法（cART）成功地减少了外周感染， HIV-1可以在中枢神经系统（CNS）中建立感染，导致发展 与HIV-1相关的认知、行为和运动缺陷 疾病（手）。一旦感染，CNS就充当难以治疗的病毒储库， 根除单核细胞吞噬细胞（MP，例如，血管周围的巨噬细胞和小胶质细胞）是 免疫特权中枢神经系统中的重要储库。拟议的研究旨在 解决中枢神经系统中HIV感染的独特动力学，探索新的治疗策略 该靶向MP，确保穿过血脑屏障（BBB）的可行递送，以消除HIV 储库和减少炎症。MP中HIV诱导的激活和病毒复制相关 这些目标是我们正在进行的新方法的重点，通过多种药理学 剂.这些方法包括设计和开发：1）MP特异性核糖核苷 链终止剂（rNCT）及其磷酸盐前药，和2）NADPH氧化酶（NOX）抑制剂 和3）JAK抑制剂，其阻断/中断 MP并能减轻炎症。将分析选定的治疗剂的体外 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， 治疗指数这些将在体内进行评价，以评估CNS药理学和反应 （包括行为和病理学）与使用两种不同的逆转录病毒CNS动物模型的治疗的关系 我们先前建立了包括颅内注射HIV-1的SCID小鼠模型 感染MP的猕猴模型和感染SIVmac 239的猕猴模型。这些研究的结果将 确定新的连续性治疗策略，与当前的cART一起， 改善MP的靶向治疗。最终目标是抑制病毒并消除这些艾滋病毒- 1 CNS中的储库，这应该导致改进的治疗，以降低发展的风险 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.