National Institute on Drug Abuse 5R01DA056261-05

The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis

This NIH grant funds research to understand how methamphetamine use increases HIV-infected monocyte migration into the brain, contributing to neurocognitive disorders in people with HIV. The study focuses on chemokine receptors CXCR7 and CXCR4 as potential therapeutic targets.

Description

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, partly via chemokine-induced transmigration of infected and uninfected CD14+CD16+ monocytes across the blood-brain barrier (BBB), contributing to viral reservoirs and chronic neuroinflammation. The chemokine CXCL12 (SDF-1) is constitutively expressed at low levels in the CNS and is increased in PWH, suggesting it contributes to monocyte influx. CXCR7 (ACKR3), an atypical chemokine receptor for CXCL12, is expressed on monocytes and contributes to transmigration along with CXCR4. Preliminary data indicate meth increases CXCL12-induced transmigration of monocytes. The hypothesis is that CXCR7 and/or CXCR4 contribute to meth-mediated increases in monocyte transmigration, especially of HIV+ cells, making CXCR7 a potential therapeutic target for HIV-NCI in PWH with meth use disorder. The study will use in vitro BBB models and in vivo macaque models to analyze effects on transmigration, receptor expression, signaling, and cell accumulation.

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