Therapeutic potential of interferon (IFN)-beta for HIV-associated neurocognitive disorders (HAND) in opioid users

干扰素 (IFN)-β 对阿片类药物使用者的 HIV 相关神经认知障碍 (HAND) 的治疗潜力

• 批准号: 9411197
• 负责人: Ling Cao
• 金额: $ 18.54万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411197
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Animal Model; Anti-Retroviral Agents; Antiviral Response; Area; Astrocytes; Astrocytosis; Behavior; Biological Models; Brain; Cells; Clinical; Cognitive; Cognitive deficits; Comorbidity; Corpus striatum structure; Data; Dendrites; Development; Disease; Drug abuse; Encephalopathies; Exhibits; Genes; Glial Fibrillary Acidic Protein; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Highly Active Antiretroviral Therapy; Hippocampus (Brain); Human; IFNAR1 gene; Immune; Immunologic Deficiency Syndromes; Individual; Infection; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Investigation; Learning; Measures; Mediating; Memory; Modeling; Morphine; Murine Acquired Immunodeficiency Syndrome; Mus; Neuraxis; Neurological outcome; Opioid; Pathogenesis; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Production; Proteins; Reporting; Risk; Rodent Model; Role; Severities; Severity of illness; Symptoms; Testing; Therapeutic; Time; Transgenic Organisms; Translating; Type I Epithelial Receptor Cell; Viral; Viral Load result; Virus; Virus Diseases; Zidovudine; behavioral impairment; frontal lobe; improved; innovation; mouse model; multiple sclerosis treatment; nervous system disorder; neuron loss; neurotoxicity; novel; novel strategies; opioid use; prevent; promoter; receptor; response; subcutaneous

Summary Opioid drug abuse significantly increases the risk and severity of HIV-associated neurocognitive disorders (HANDs). However, the understanding of the interaction between opioids and HIV infection is far from complete. In the current study, we propose to explore the potential of investigating the interaction between opioids and HIV infection by combining two distinct, but complementary, rodent models: 1) the LP-BM5 model, in which a murine retroviral isolate induces a severe immunodeficiency syndrome (murine AIDS, MAIDS) as well as CNS encephalopathy and cognitive deficits in susceptible C57BL/6 (B6) mice; and 2) HIV gp120 transgenic (HIV gp120tg) mice, in which the HIV envelope protein gp120 is produced under the control of the glial fibrillary acidic protein promoter in astrocytes. By combining these two models, we can further examine the effects of morphine on HANDs-like CNS damage in the context of a live viral infection-induced immunodeficiency condition. Further, the type I interferon (IFN) response is a critical anti-viral innate immune mechanism and mediated by IFNα and IFNβ through their common receptor, IFNAR. Systemically, HIV-1 can manipulate the host cell type I IFN response in order to establish persistent infection. However, the role of type I IFNs in HANDs is still not well delineated, and the involvement of type I IFNs in HANDs amongst opioid users remains unclear. We propose to further delineate the roles of type I IFNs in co-existing HANDs and morphine use and examine the therapeutic potential of IFNβ through the use of the murine models mentioned above. We hypothesize that the lack of an efficient type I IFN response in the hippocampus contributes to morphine-potentiated infection-induced neurological disorders and that by supplying IFNβ, we can reduce morphine's detrimental effects and improve neurological outcomes. This central hypothesis will be tested through two Specific Aims. Aim 1. Characterize the type I IFN response in HIVgp120tg mice (using wild type B6 mice as controls) that are subjected to LP-BM5 infection ± morphine treatment. We will examine HIV-sensitive areas, the hippocampus and the striatum, in comparison to the less sensitive frontal lobe. The interactive effects between infection, gp120, and morphine on the type I IFN response will be evaluated. Aim 2. Determine the therapeutic potential of IFNβ in morphine-potentiated neuropathological responses. Through this study, we will establish a unique small animal model system to study HIV/HANDs and the effect of opioid on HANDs. Further, we are advancing towards a novel adjuvant treatment for HANDs in HIV-infected opioid users. It should be noted that IFNβ has been successfully used as a disease-modifying treatment for multiple sclerosis. As such, our results could relatively rapidly translate to clinical usage.

总结