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

针对巨噬细胞/小胶质细胞的治疗方法根除中枢神经系统 HIV-1 病毒库

基本信息

批准号：
9247721
负责人：
Raymond Felix Schinazi
金额：
$ 72.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-18 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247721
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Behavior Behavioral Biochemical Biochemistry Biological Biological Assay Blood - brain barrier anatomy Brain CD4 Positive T Lymphocytes Chronic Clinical DNA biosynthesis Development Dose Drug Design Elements Ensure Environment Enzymes Equus caballus Exhibits FDA approved Genetic Transcription Goals HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Immune In Vitro Infection Inflammation Inflammatory Injectable Interruption Janus kinase Lead Libraries Link Macaca Microglia Modeling Mononuclear Morbidity - disease rate Mus NADPH Oxidase Neuraxis Nucleosides Outcome Partition Coefficient Pathology Penetration Peripheral Phagocytes Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Predisposition Prevalence Prodrugs Production Proteins Protocols documentation Regimen Retroviridae Ribonucleosides Risk SAM Domain SCID Mice Superoxides Testing Therapeutic Therapeutic Agents Toxic effect Toxicology Viral Viral reservoir Virus Virus Replication antiretroviral therapy cognitive development design drug candidate improved in vivo in vivo Model inflammatory milieu inhibitor/antagonist inorganic phosphate kinase inhibitor macrophage monocyte mortality motor deficit mouse model mutant neurotoxic nonhuman primate novel therapeutic intervention novel therapeutics nucleoside triphosphate prevent public health relevance response small molecule success targeted treatment therapeutic target therapy design

项目摘要

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.

描述（由适用提供）：尽管合并的抗逆转录病毒疗法（CART）成功地减少了周围感染，但HIV-1仍可以在中枢神经系统（CNS）中建立感染，从而导致认知，行为和运动的发展，从而定义了与HIV-1相关的神经认知疾病（手）。一旦感染，中枢神经系统就会充当一个难以治疗和放射酸酯的病毒储层。单核吞噬细胞（例如MPS，例如，血管周围巨噬细胞和小胶质细胞）是免疫挑战中心的重要储层。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MP的新型治疗策略，确保在整个血脑屏障（BBB）中可行递送（BBB），以消除HIV储量并减少感染。 MPS中HIV诱导的激活和病毒复制是通过多种药物接触的相关靶标。 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 infection, MP-specific ribbonnucleoside chain terminators and their phosphate prodrugs for increased delivery to the CNS, and NADPH oxide inhibitors that are known to cross the BBB which indirectly could reduce NFκB依赖性HIV-1转录。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。将在体内评估满足效力标准的特定小分子候选物，以评估使用两个不同的逆转录病毒CNS动物模型评估CNS药物和反应（包括行为和病理）对治疗的治疗：我们先前已经建立的：SCID小鼠在内部注射了HIV-1内注射HIV-1感染的MPS，以及CD4+脱离型猕猴模型，并与SIV MACACE INVECTACH MACACEMACE INDECEDSIVSIV。这些研究的结果将确定新的辅助治疗策略，这些治疗策略与当前的手推车一起可以改善对国会议员的靶向治疗。最终目标是抑制中枢神经系统中的病毒并消除这些HIV-1储层，这些储层应导致改进的治疗方法，以降低发育中心的风险。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors.

DOI：
10.1097/coh.0000000000000007
发表时间：
2013-11
期刊：
Current opinion in HIV and AIDS
影响因子：
4.1
作者：
Hurwitz SJ;Schinazi RF
通讯作者：
Schinazi RF

The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model.

DOI：
10.1016/j.nbd.2016.02.007
发表时间：
2016-08
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Haile WB;Gavegnano C;Tao S;Jiang Y;Schinazi RF;Tyor WR
通讯作者：
Tyor WR

HIV-associated neurocognitive disorders: Five new things.

艾滋病毒相关的神经认知障碍：五种新事物。

DOI：
10.1212/cpj.0000000000000117
发表时间：
2015
期刊：
Neurology. Clinical practice
影响因子：
0
作者：
Rumbaugh,JeffreyA;Tyor,William
通讯作者：
Tyor,William

HIV latency reversal research and the potential effects on the central nervous system: is concern warranted?

HIV潜伏期逆转研究及其对中枢神经系统的潜在影响：值得关注吗？

DOI：
10.7448/ias.19.1.21008
发表时间：
2016
期刊：
Journal of the International AIDS Society
影响因子：
6
作者：
Anderson,AlbertM;Schinazi,RaymondF;Tyor,WilliamR
通讯作者：
Tyor,WilliamR

Synthesis and evaluation of Janus type nucleosides as potential HCV NS5B polymerase inhibitors.

DOI：
10.1016/j.bmcl.2013.03.077
发表时间：
2013-06-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Zhou, Longhu;Amblard, Franck;Zhang, Hongwang;McBrayer, Tamara R.;Detorio, Mervi A.;Whitaker, Tony;Coats, Steven J.;Schinazi, Raymond F.
通讯作者：
Schinazi, Raymond F.