Despite aggressive use of combination antiretroviral (ARV) therapy, HIV infection promotes encephalitis and neurobehavioral impairment, collectively termed neuroAIDS in about half of infected individuals. Poor penetration of ARVs across the blood brain barrier likely contributes to persistence of HIV and resultant chronic brain inflammation, despite systemic effectiveness. Opiate drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV- infected persons. Yet, despite HIV and drug abuse being inextricably linked, morphine- and HIV- interactive effects on the actual penetration of therapeutic drugs (i.e., ARVs) are not well studied. Understanding how antiretroviral penetration across the BBB into CNS is altered in the setting of opioid abuse may lead to an understanding of why these patients have more severe neurocognitive impairment and may ultimately lead to the development of better therapeutic drug regimens for neuroAIDS. The long-term goal of this project is to understand the effects of opiate abuse and HIV-1 on the BBB and on antiretroviral penetration across the BBB into the brain. Approach: Using a doxycycline inducible HIV-1 Tat mouse model, the effects of morphine HIV-1 Tat exposure on barrier permeability and antiretroviral penetration into the brain will be assessed. Additionally, factors affecting antiretroviral tissue penetration, such as the expression and function of drug efflux proteins, will also be measured in this model. In vitro BBB studies will be performed to compliment and expand upon the in vivo studies.
Opioid drug abuse exacerbates HIV-associated neurocognitive deficits and other neurodegenerative effects. This grant proposes to use both in vitro and in vivo models to examine the mechanisms of HIV-opioid exposure on blood brain barrier structure, integrity and function as well as how these changes affect the penetration of therapeutic drugs into the brain. A more thorough understanding of events underlying damage to the blood brain barrier may lead to the development of better neuropenetrating therapies.
