Towards Suppression and Elimination of HIV in the CNS

抑制和消除中枢神经系统中的艾滋病毒

• 批准号: 10311081
• 负责人: Raymond Felix Schinazi
• 金额: $ 67.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311081
• 关键词: Address; Animal Model; Behavior; Behavioral; Biochemistry; Biological Models; Biology; Blood; Blood - brain barrier anatomy; CD4 Positive T Lymphocytes; Cell Death; Cell model; Cells; Development; Dose; Ensure; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Immune; In Vitro; Individual; Infection; Inflammation; Interruption; Kinetics; Knowledge; Lead; Lymphocyte; Macaca; Macaca mulatta; Maintenance; Microglia; Modeling; Mononuclear; Mus; Myelogenous; Myeloid Cells; NADPH Oxidase; Neuraxis; Pathology; Peripheral; Persons; Phagocytes; Pharmacology; Phase II Clinical Trials; Phenotype; Physiological; Play; Prodrugs; Property; Regimen; Resources; Retroviridae; Ribonucleosides; Risk; Role; SCID Mice; SIV; Safety; Series; System; T-Cell Depletion; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Toxicology; Viral reservoir; Virus; Virus Replication; Withholding Treatment; analog; animal model development; anti-viral efficacy; antiretroviral therapy; base; cell type; chemical synthesis; chronic infection; cognitive development; design; improved; in vivo; in vivo Model; inhibitor; innovation; inorganic phosphate; lead candidate; macrophage; monocyte; motor deficit; mouse model; nanomolar; nonhuman primate; novel; novel strategies; novel therapeutic intervention; novel therapeutics; response; stem cells; success; targeted treatment; trafficking; treatment response; viral rebound

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.

项目摘要/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，但 HIV-1可以在中枢神经系统（CNS）中建立感染，从而导致发展 与HIV-1相关的神经认知相关的认知，行为和运动缺陷 疾病（手）。一旦被感染，中枢神经系统就会充当一个难以治疗的病毒储层 根除。单核吞噬细胞（MP，例如，血管周围巨噬细胞和小胶质细胞）是 免疫挑战的中枢神经系统中的重要储层。拟议的研究旨在 解决中枢神经系统中HIV感染的独特动态并探索新颖的治疗策略 该目标MP，确保在血脑屏障（BBB）上可行的可行递送以消除HIV 水库并减少炎症。 HIV引起的MP中的激活和病毒复制是相关的 通过多种药理的目标是我们正在进行的新颖方法的重点 代理商。这些方法包括：1）MP特异性核糖核苷的设计和开发 链终端（RNCTS）及其磷酸盐前药，2）NADPH氧化酶（NOX）抑制剂 跨越BBB和目标MP，以及3）阻断/中断激活状态的JAK抑制剂 MP并可以减少炎症。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。 我们最近确定了低或亚纳摩尔MP特异性HIV抑制剂 治疗指数。这些将在体内评估以评估CNS药理和反应 （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HIV-1颅内注射的SCID小鼠模型 感染的MP和被SIVMAC239感染的猕猴模型。这些研究的结果将 确定新的辅助治疗策略，并与当前的购物车一起提供 改善了对MP的靶向疗法。最终目标是抑制病毒并消除这些HIV- 中枢神经系统中的1个水库应导致改进的治疗方法，以降低发展的风险 手。