The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis

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.

Grant Number: 5R01DA056261-04
NIH Institute/Center: NIH
Principal Investigator: Joan Berman