The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis

甲基苯丙胺对 CXCL12 介导的 HIV 神经发病机制的影响

• 批准号: 10547875
• 负责人: Joan Weinberger Berman
• 金额: $ 42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547875
• 关键词: Adhesions; Astrocytes; B-Lymphocytes; Behavior Disorders; Biological Process; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CCL2 gene; CD14 gene; CXCL12 gene; CXCR4 gene; Cells; Chemotaxis; Chronic; Cognition Disorders; Data; Defect; Development; Embryo; Endothelial Cells; Environment; Exposure to; FCGR3B gene; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Hand; Heart; Heterodimerization; Human; Impaired cognition; In Vitro; Infection; Inflammatory; Intervention; Laboratories; Macaca; Mediating; Methamphetamine; Methamphetamine use disorder; Modeling; Mus; Neurocognitive Deficit; Neurons; Neuropathogenesis; Peripheral; Persons; Population; Prevalence; Process; Production; Public Health; Quality of life; Reporting; Role; SIV; Signal Pathway; Signal Transduction; Stromal Cell-Derived Factor 1; Substance Use Disorder; Surface; T-Lymphocyte; Tissues; Up-Regulation; Viral; Viral reservoir; Virus; antiretroviral therapy; beta-arrestin; brain cell; chemokine; chemokine receptor; comorbidity; cytokine; extracellular; in vivo; macrophage; methamphetamine effect; methamphetamine use; monocyte; motor disorder; neuroinflammation; neurotoxic; novel; receptor; response; therapeutic target; therapy development

The goal of this proposal is to characterize mechanisms by which methamphetamine (meth) increases HIV infected CD14+CD16+ monocyte transmigration across the BBB to CXCL12, increasing perivascular and parenchymal infected macrophage accumulation in the CNS of people with HIV (PWH) with meth use disorder. There is increased prevalence of HIV associated neurocognitive disorders or impairment (HAND, HIV-NCI) in PWH, even with antiretroviral therapy (ART), greatly impacting their quality of life. A significant number of people with meth use disorder are also infected with HIV, with increased neurocognitive impairments reported in active meth using PWH. The mechanisms by which meth use disorder increases HIV-NCI in PWH on ART are not completely characterized, impeding the development of interventional strategies to reduce or eliminate cognitive dysfunctions in this population. HIV enters the CNS early after initial infection, in part, by chemokine induced transmigration of infected and uninfected CD14+CD16+ monocytes across the blood brain barrier (BBB), contributing to the replenishment of viral reservoirs and chronic low level neuroinflammation that characterize HIV-NCI. The chemokine CXCL12 (SDF-1) is constitutively expressed at low levels in the CNS and is increased in the CNS of PWH, suggesting that this chemokine contributes to influx of uninfected and infected CD14+CD16+ monocytes into the CNS. Our laboratory reported the novel finding that CXCR7 or ACKR3, an atypical chemokine receptor for CXCL12, is expressed on the surface of uninfected and HIV infected CD14+CD16+ monocytes and contributes, along with CXCR4, to the transmigration of these cells across the BBB to CXCL12. Our preliminary data indicate that meth increases CXCL12 induced transmigration of both uninfected and HIV infected CD14+CD16+ monocytes. The role of CXCR7 and/or CXCR4 in these meth mediated effects, particularly in increased transmigration of CD14+CD16+ monocytes that harbor HIV (HIV+) compared to cells that are exposed to, but do not harbor, virus (HIVexp), is the focus of this proposal. We hypothesize that CXCR7 and/or CXCR4 contribute to meth mediated increases in CXCL12 induced HIV infected CD14+CD16+ monocyte transmigration, including the preferential transmigration of HIV+ cells compared to HIVexp cells. Thus, CXCR7 may be a therapeutic target for HIV-NCI treatment in PWH with meth use disorder. We will use our in vitro human BBB model to characterize the role of CXCR7 and/or CXCR4 in meth mediated effects on transmigration and on cells of the BBB. We will determine effects of meth on CXCR7 and/or CXCR4 expression, and on CXCL12 induced signaling, adhesion, chemotaxis, and invasion in uninfected/HIV infected CD14+CD16+ monocytes. The in vivo effects of meth on monocyte influx into the infected CNS will be examined in CNS tissue sections from meth treated SIV infected macaques by immunohistochemical analyses of BBB expression of CXCL12, and perivascular and parenchymal accumulation of CXCR7 and/or CXCR4 expressing monocytes/macrophages.

本提案的目标是表征甲基苯丙胺（冰毒）增加艾滋病毒的机制