This is a R21 application in response to RFA-AA-07-016 entitled """"""""Mechanisms of Nervous System Dysfunction: Impact of Alcohol Abuse on HIV-1 Neuropathogenesis (R21)"""""""", which was issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The fundamental goal of this R21 application is to explore the feasibility of using our doxycycline (Dox) inducible and brain-targeted HIV-1 Tat transgenic mouse model for studies on alcohol abuse-HIV interaction and its role in HIV-1 neuropathogenesis. Alcohol abuse often occurs prior to and after HIV infection. Several studies suggest that alcohol and HIV-1 Tat protein, a viral protein released during HIV-1 infection, often synergize to exhibit similar neurotoxic properties. Despite this progress, the functional consequences of alcohol interaction with Tat in HIV neuropathogenesis are not well understood. Meanwhile, most of these studies are performed in vitro and the experimental design did not take into consideration the fact that HIV-associated neuropathogenesis is a result of HIV interaction with all brain cells, including neurons, astrocytes and endothelial cells. We have recently established a HIV-1 Tat transgenic mouse model in which Tat expression can be induced to exclusively express in the brain, and demonstrated that expression of HIV-1 Tat protein in the brain in the absence of HIV-1 infection is sufficient to induce neurobehavioral and neuropathologies that recapitulate some important features in the brain of HIV-1-infected individuals (Kim et al., Am. J. Path, 162:1693-707, 2003). Thus, in this exploratory R21 phase application, we propose to characterize HIV-1 Tat interaction with alcohol abuse in vivo and determine the optimal timing of alcohol exposure and Tat expression in inducing neuropathologies. This will be in preparation for a R01 application in which the underlying cellular and molecular mechanisms and possible interventions of this neurotoxicity synergy between Tat and alcohol will be determined. The proposed research plan involves induction of HIV-1 Tat protein expression at different ages of mice that have been pre-exposed to alcohol in both chronic and binge fashions. Immunohistochemistry staining will be used to monitor changes of brain pathologies including Tat-induced extracellular accumulation of low-density lipoprotein receptor-related protein (LRP) ligands, the CNS infiltration of macrophages/monocytes, and neuron death, while neurobehavioral consequences such as locomotor function and conditioned place preference (CPP) will be determined. ? ? Public Health Relevance: Individuals with alcohol abuse are more likely to contract HIV, and rates of HIV infection are much higher in alcohol-abusing subjects. Both alcohol abuse and HIV infection often causes a number of brain diseases and affects the ability of people to care for themselves and thus the quality of their daily life. The social and economic impact can not be overemphasized. The current study seeks to establish a small rodent model to characterize alcohol interaction with HIV-1 Tat and ultimately develop therapeutic interventions to prevent and treat neurological diseases resulting from alcohol abuse and HIV infection. ? ? ?
