Human/Animal Brain Chimera in drugs of abuse and HIV

Abstract: Drugs of abuse are a significant comorbidity among people living with HIV. Methamphetamine
(Meth), in particular, is a potent psychostimulant frequently abused in the HIV/AIDS population. Both HIV and
Meth are risk factors for cognitive decline even in the era of combination antiretroviral therapy (cART). The
mechanism(s) that drive and/or contribute to this cognitive decline, collectively known as HIV-Associated
Neurocognitive Impairment (HAND), are not entirely clear nor is the impact of Meth on HIV reservoir. Meth itself
enhances HIV replication. We will use two innovative humanized animal models to address the interface between
glial cells, Meth and HIV reservoir. huAstro/HuPBMC mice, generated by engraftment of IPSC-astrocytes into
NSG mice, can uniquely address the role of astrocytes as a reservoir for HIV and in HIV egress out of the brain
to peripheral organs (Aim 1) and define the effect of Meth with or without HIV on prototypical functions of
astrocyte and brain homeostasis (Aim 2). We focus on astrocytes because they constitute a significant resident
brain cell population and perform vital functions to maintain brain homeostasis. The HuCD34/NPC model (CD34
humanized mice engrafted with neuronal progenitor cells (NPCs) will be used to assess the role of Meth on HIV
evolution over time in the CNS and peripheral organs (Aim 3). Combining these two models with the resources
of the Translational Methamphetamine AIDS Research Center (TMARC) and the NIDA center for genetic studies
at Rutgers and cell repository (RUDCR) to reprogram lymphocytes from Meth/HIV donors to generate IPSC then
NPC and/or IPSC-astrocytes as targeted for in vitro and in vivo studies provides a powerful tool to address our
central hypothesis that Meth mediates a greater HIV reservoir in astrocytes and egress into peripheral organs
(Aim 1), dysregulate astrocytes to disrupt brain homeostasis (Aim 2), and promote s greater extent of viral
evolution within the CNS (Aim 3). Together, these studies are responsive to NIDA HIV research high priority
areas and will advance our knowledge regarding the role of drugs of abuse on HIV reservoir, evolution, and
neuropathogenesis to inform better strategies to uniquely address persistent HIV among the HIV positive drug
abusing population.

Grant Number: 5R01DA055497-04
NIH Institute/Center: NIH
Principal Investigator: Lena Al-Harthi