HIV-infection and opioid injection drug abuse are co-morbid diseases, with opioid use involved in both the spread and pathogenesis of the virus, and may worsen neurocognitive impairments experienced by these patients. Although combined antiretroviral therapy is increasing the life-span of infected individuals, these treatments have not been successful in reducing HIV-1 associated neurocognitive disorders (HAND), which predominates in areas of the basal ganglia, such as the striatum, as well as the hippocampus and areas of the frontal cortex. Thus, better therapies to alleviate central nervous system (CNS) consequences of HIV-1 infection are needed. Our laboratory is interested in identifying convergent mechanisms between HIV-1 proteins and morphine, the active metabolite of heroin in the CNS, that contribute to the pathology of HIV-1 infection. The CC chemokine receptor 5 (CCR5) may be one such link between drug abuse and disease. Not only is it involved in viral infection of host cells, but in the CNS, seems to act as an inflammatory mediator of HIV-1 Tat signaling. This receptor also has intimate interactions with the opioid system, being regulated by both opioid receptors and opioid drugs, and as such is a good target for the study of opioid-HIV-1 interactions. Preliminary experiments suggest that pharmacological inhibition of CCR5, by maraviroc, is neuroprotective against collective Tat and morphine toxicity. Maraviroc is also sufficient to reduce glial NF-?B p65 activation and chemokine release, confirming that CCR5 is a critical mediator of glial inflammatory signaling. With the evidence that has been obtained, it i hypothesized that interference with CCR5 will alleviate HIV-1 Tat and morphine induced neuronal injury and motor impairments. The proposed studies will be accomplished using genetic manipulation of CCR5, instead of pharmacological tools. A chimera mouse is being developed through breeding of Tat-transgenic mice with CCR5 null mice to examine the effects of chronic doses of viral proteins and opioids on glial and neuronal function. This will be performed by completing the following two specific aims: 1) Assess the effects of CCR5 ablation on glial inflammation and neuronal injury in vivo in inducible Tat-transgenic mice treated with morphine, and 2) Examine motor deficits in inducible Tat-transgenic mice administered morphine and determine if CCR5 deletion can abate these changes. This will be performed using immunohistochemistry, Golgi-Kopsch impregnation, microscopy, and behavioral assessments of rotarod performance, grip strength, and gait analysis to determine if CCR5 is a good therapeutic candidate to alleviate the consequences of opioid drug abuse and HIV-1 interactions.
Needle sharing in injection drug abusers, such as heroin users, leads to the spread of diseases including HIV- 1. In addition to leading to the spread of this disease, heroin actually makes the disease worse;heroin abusers have more inflammation in the brain and more neurological problems. The purpose of this project is to study a specific protein, CCR5, that may be involved in the interactions between HIV-1 and drug abuse and that may contribute to enhanced deficits in these individual.
