Dopamine system as reporter of HIV status and inflammation in Meth abusers

多巴胺系统作为冰毒滥用者艾滋病毒状况和炎症的报告者

• 批准号: 10343776
• 负责人: Maria Cecilia Garibaldi Marcondes
• 金额: $ 43.2万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343776
• 关键词: Affect; Age; Alleles; Anti-Retroviral Agents; Basic Science; Biological Markers; Blood; Brain; CCR5 gene; Cells; Central Nervous System Diseases; Characteristics; Clinical; Cognitive; Cognitive deficits; Data; Development; Dopamine; Dopamine Receptor; Encephalitis; Environment; Equilibrium; Exposure to; Gene Frequency; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Goals; HIV; HIV Infections; Human; IL6 gene; Immune; Immunologic Markers; Individual; Individual Differences; Inflammation; Inflammatory; Knowledge; Life Expectancy; METH abuser; Methamphetamine; Monitor; Neuraxis; Neuroimmune; Neurologic; Neurologic Deficit; Neurological outcome; Neuropsychology; Neurotransmitters; Nucleotides; Organ; Outcome; Pathogenesis; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Process; Receptor Gene; Reporter; Rewards; Risk; Risk Factors; Role; Sampling; Severities; Signal Transduction; Single Nucleotide Polymorphism; Statistical Models; Syndrome; Testing; Therapeutic; Time; Treatment Efficacy; Viral; Virus; Virus Receptors; Virus Replication; biomarker signature; cognitive development; cognitive function; cognitive performance; comorbidity; design; dopamine system; drug abuser; experience; experimental study; individual variation; inflammatory marker; mathematical model; methamphetamine abuse; methamphetamine user; models and simulation; molecular subtypes; neuroAIDS; neuropathology; peripheral blood; programmed cell death protein 1; psychologic; screening; sex; substance use; tool; translational applications; translational impact

Dopamine system as reporter of HIV status and inflammation in Meth abusers HIV life-expectancy has increased with anti-retrovirals, but the consequences of the virus in end-organs such as the Central Nervous System (CNS) have not been mitigated. Moreover, co-morbidities such as substance use can aggravate CNS disorders in HIV infection, impacting viral replication and inflammation. Methamphetamine (Meth) is a popular addictive drug associated with risk of HIV infection, and a powerful inducer of dopamine (DA), a neurotransmitter that regulates reward circuits in the brain. Inflammatory biomarkers such as plasma CD163 and IL6 levels correlate with HIV-induced cognitive deficits, including in Meth abusers. They indicate that an inflammatory process is taking place in the brain, but may not be able to predict risk of development of CNS inflammation in Meth abusers, or monitor improvements in cognitive performance in the context of HIV. Innate immune cells are the main HIV target cells in the CNS. Importantly, these cells express DA receptors (DRDs), and therefore are responsive to the hyperdopaminergic environment generated by Meth abuse. We hypothesize that the expression of molecules of the DA system, as well as inflammatory markers resulting from DA signaling, are sensitive biomarkers that may be incorporated into a panel of tools with the capacity to predict susceptibility and to assess therapeutic efficacy in the blood of HIV+ subjects that are Meth-abusers. We also hypothesize that the individual genetic background can bias the balance between D1-like and D2-like DRD subtypes, and their resulting inflammatory signatures affecting HIV latency or replication phenotypes. We propose studies in human peripheral cells that bridge basic science findings with translational applications of high impact, for screening DRD subtypes expression levels and sequence, as well as inflammatory signatures associated with these subtypes as predictors of risk to the development of cognitive deficits in Meth abusers, in the context of HIV. Our integrated approach is targeted to predict and monitor neuro-immune-viral disruptions, and generate tools to become incorporated in clinical therapeutic decisions. It will provide invaluable data to fill the existing gap in the knowledge and in the needs of markers with real-time clinical value, with the potential for critically monitoring the efficacy of therapy in the CNS, or for predicting susceptibility to disabling neurological syndromes in HIV+ individuals that are drug abusers.

多巴胺系统作为甲基安非他明滥用者HIV状态和炎症的报告者