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

描述(申请人提供)：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，但HIV-1可以在中枢神经系统(CNS)建立感染，导致与HIV-1相关的神经认知障碍(HAND)相关的认知、行为和运动障碍的发展。一旦被感染，中枢神经系统就像一个难以治疗和根除的病毒库。单核巨噬细胞(MPS，如血管周围巨噬细胞和小胶质细胞)是免疫优势中枢神经系统的重要储存库。拟议的研究旨在解决中枢神经系统中艾滋病毒感染的独特动态，并探索针对MPS的新治疗策略，确保可行的跨血脑屏障(BBB)传递，以消除艾滋病毒宿主并减少炎症。HIV诱导的MPS的激活和病毒复制是相关的靶点，将通过多种药理药物进行研究。三种独特且独立确定的策略将被作为减少MPS内HIV复制的新型治疗药物进行研究：阻断/中断MPS激活状态并可减少炎症的JAK抑制剂，MP特异性核糖核苷链终止子及其磷酸前药增加对中枢神经系统的输送，以及已知跨越血脑屏障的NADPH氧化酶抑制剂，后者可间接减少依赖于Nf8的HIV-1转录。选定的治疗药物将被分析其体外抗病毒效力，并评估生物化学、毒理学和细胞药理学。 参数。满足效力标准的特定候选小分子将在体内进行评估，以评估CNS的药理学和治疗反应(包括行为和病理)，使用我们之前建立的两个不同的逆转录病毒CNS动物模型：脑内注射HIV-1感染的MPS的SCID小鼠模型和感染SIVmac239的CD4+耗竭猕猴模型。这些研究的结果将确定新的辅助治疗策略，与目前的CART一起，可以为MPS提供更好的靶向治疗。最终目标是抑制病毒并消除中枢神经系统中这些艾滋病毒-1储存库，这将导致改进治疗方法，以降低发生手部疾病的风险(S)。

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 NF8¿- 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.