Therapeutics Targeting Macrophages/Microglia to Eradicate CNS HIV-1 Reservoirs

描述（由申请方提供）：尽管联合抗逆转录病毒治疗（cART）成功减少了外周感染，但HIV-1可在中枢神经系统（CNS）中建立感染，导致与HIV-1相关神经认知障碍（HAND）相关的认知、行为和运动缺陷。一旦被感染，CNS就像一个难以治疗和根除的病毒储存库。单核细胞吞噬细胞（MP，例如，血管周围巨噬细胞和小胶质细胞）是免疫豁免CNS中的重要储库。拟议的研究旨在解决CNS中HIV感染的独特动力学，并探索靶向MP的新型治疗策略，确保穿过血脑屏障（BBB）的可行递送，以消除HIV储库并减少炎症。HIV诱导的活化和MP中的病毒复制是将通过多种药理学试剂接近的相关靶点。将研究三种独特且独立鉴定的策略作为新型治疗剂，以减少MP内的HIV复制：阻断/中断MP活化状态并可减少炎症的JAK抑制剂、MP特异性核糖核苷链终止剂及其磷酸盐前药，用于增加向CNS的递送，和NADPH氧化酶抑制剂，已知可穿过BBB，间接降低NFκ B依赖性HIV-1转录。将分析选定的治疗药物的体外抗病毒效力，并评估生物化学、毒理学和细胞药理学 参数将使用我们先前建立的两种不同的逆转录病毒CNS动物模型（颅内注射HIV-1感染MP的SCID小鼠模型和感染SIVmac 239的CD 4+耗竭猕猴模型），在体内评价符合效力标准的特定小分子候选物，以评估CNS药理学和对治疗的反应（包括行为和病理学）。这些研究的结果将确定新的连续性治疗策略，这些策略与当前的cART一起可以为MP提供改进的靶向治疗。最终目标是抑制病毒并消除CNS中的这些HIV-1储库，这将导致改善治疗以降低发生HAND的风险。

DESCRIPTION (provided by applicant): 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 (MPs, 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 MPs, ensure viable delivery across the blood-brain barrier (BBB) to eliminate the HIV reservoir and reduce inflammation. HIV-induced activation and viral replication in MPs are relevant targets that will be approached through multiple pharmacological agents. Three unique and independently identified strategies will be investigated as novel therapeutic agents to reduce HIV replication within MPs: JAK inhibitors that block/interrupt the activation state of MPs and that can reduce inflammation, MP-specific ribonucleoside chain terminators and their phosphate prodrugs for increased delivery to the CNS, and NADPH oxidase inhibitors that are known to cross the BBB which indirectly could reduce NFκB-dependent HIV-1 transcription. Selected therapeutic agents will be analyzed for their in vitro antiviral potency, and to assess biochemistry, toxicology, and cellular pharmacology parameters. Specific small molecule candidates which fulfill potency criteria 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: SCID mouse model intracranially injected with HIV-1 infected MPs, and CD4+ depleted macaque model infected with SIVmac239. Results from these studies will identify new adjunctive therapeutic strategies which together with current cART could provide improved targeted therapy to MPs. 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.