Despite aggressive use of combination antiretroviral therapy, HIV infection is associated with cognitive and
neurobehavioral impairment, collectively termed neuroHIV. HIV and opiates are independently associated with
blood brain barrier (BBB) dysfunction, alterations in inflammatory signaling, and cognitive and motor deficits.
The HIV viral protein Tat is thought to mediate much of the HIV-associated damage within the brain. This
proposal will use both a Tat transgenic mouse model and a murine tropic HIV-infected mouse model. The Tat
transgenic mouse model expresses HIV-1 Tat driven by a GFAP promotor, which limits expression to the CNS.
The two models will be used to examine the effects of HIV and morphine in vivo. Our central hypothesis is that
opiates compromise BBB function and contribute to neuropathology through complex mechanisms which
include enhancing paracellular flux, while paradoxically decreasing net flux of antiretrovirals across the barrier,
increasing infiltration of monocytes, and increasing inflammatory signals within the brain. We will address our
hypotheses with the following specific aims. Aim 1. Define the effects of opiates ± HIV-1 Tat and HIV infection
on BBB integrity and function and on region-specific impact on antiretrovirals and morphine concentrations
within the brain. Aim 2. Characterize regional differences in the interplay between opiates ± HIV/HIV-1 Tat and
ARVs on macrophage infiltration into the CNS and on proinflammatory cytokine production the CNS. These
studies will define and relate the effects of opiates and/or HIV-1 on regional drug accumulation, BBB integrity,
drug metabolism/efflux, and immune cell trafficking into and inflammatory signals within the brain. Better
understanding of this dynamic interplay, with specific focus on antiretroviral brain concentrations, will improve
the current therapeutic approaches for the HIV patients who use opioids (for licit or illicit use).
The long-term goal is to understand how opiates limit ARV therapeutic efficacy within the brain in the setting of
HIV and to identify targets for therapeutic development to eliminate the negative effects of opiates/HIV on