Neurological diseases associated with HIV-l infection range from AIDS dementia complex to mild peripheral neuropathy. Since the brain is a principal target organ not only for HIV- 1, but also for drugs of abuse such as cocaine, it is possible that recreational drugs may play a significant role in the pathogenesis of HIV-l induced encephalopathy. The purpose of this small grant application is to investigate the molecular mechanisms underlying the role of cocaine in the pathogenesis of encephalopathy in HIV infected subjects Within days of infection HIV-l can enter the CNS where several resident cells can serve as reservoirs for virus. Recently a unique HIV-l entry co-receptor, CC-CKR5, and a trio of HIV-l specific suppressor chemokines namely, RANTES, MIP-lalpha and MIP-lbeta, were identified. Both the entry co-receptor and the suppressor chemokines are specific for macrophage-tropic viral isolates that predominate early during HIV-l infections. Since cocaine is a significant cofactor in susceptibility to and progression of HIV infections, we hypothesize that cocaine may mediate these effects through modulation of the expression of chemokines and/or the HIV-l entry co-receptor resulting in encephalopathy. Specifically, we shall examine the expression of the genes for the chemokines and the entry co-receptor as well as the synthesis of these chemohnes by CD4+ and CD8+ lymphocyte subpopulations cultured + cocaine. Study subjects will consist of HIV-l infected patients stratified on the basis of the presence or absence of encephalopathy and the active use of cocaine. Patients will be compared to age and sex matched normal controls. Our preliminary study showed that morphine significantly suppressed MIP-1beta mRNA expression by normal lymphocytes thus supporting the feasibility of the current proposal. However since cocaine has been directly linked to susceptibility to and progression of HIV-1 infection, the current proposal will focus on this drug of abuse. These studies will elucidate the molecular mechanisms of cocaine-associated encephalopathy in HIV-1 infection. Further, this project will attempt to develop novel therapeutic strategies including the use of inexpensive synthetic blockers for the HIV-1 entry co-receptor and vaccines to stimulate the production of HIV-1 suppressive chemokines to prevent and/or control the pathagensis of HIV-1 infection.
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