Drug abuse directly contributes to one-third of all HIV-1 infections in the United States. While epidemiological data have demonstrated that opioid abuse is a risk factor for HIV-1 infection and progression to AIDS, accumulating evidence reveals possible synergistic interactions between the mu opioid (MOR) and CCR5 chemokine receptors in this pathologic process. Therefore, a thorough understanding of the neural pathways likely involved in opioid enhancement of HIV-1 infection is essential. Our hypothesis is that bivalent ligands containing both a MOR antagonist and a CCR5 antagonist may serve as chemical probes to study the interaction of these two major receptors with respect to HIV-1 infection enhanced by opioid abuse. The oligomerization of opioid receptors and CCR5 uniquely affects immune cell function and their molecular interactions may underlie their apparently synergistic effects in the CNS. Bivalent ligands have been shown to be powerful molecular tools for characterization of G-protein coupled receptor (GPCR) protein-protein interactions, to interfere with normal function related to these interactions, or even to treat diseases by targeting such interactions. We believe a ligand of this kind may not only serve as a pharmacological probe to help clarify the mechanism of opioid abuse-enhanced HIV-1 infection and understand the neuropathogenesis of dementia due to drug abuse and HIV-1 infection, but may also be therapeutic in repressing this enhanced HIV-1 infection. Therefore, the long-term goals of this project are to elucidate the molecular mechanism of opioid-enhanced HIV-1 infection by using such bivalent ligands, and to explore the potential application of these ligands for the treatment of opioid abuse and HIV-1 infection-related dementia.
The specific aims of this proposal are to: 1) characterize the bivalent ligands in cellular binding and functional assays, at both acute and chronic conditions;2) examine the efficacy of bivalent ligands in blocking HIV-1 entry and infectivity via CCR5 and MOR-CCR5 interactions;and 3) study the pathogenesis of neuroAIDS by applying the bivalent ligand probes.
Morphine, along with heroin and other opioids, has been shown to enhance HIV-1 infection. This proposal will apply novel chemical probes to investigate the molecular mechanism of opioid abuse enhanced HIV-1 infection in an effort to understand the neuropathogenesis of dementia due to drug abuse and HIV-1 infection. We will use the multidisciplinary tools of neuropharmacology, molecular and cellular biology, medicinal chemistry, and immunochemistry to explore the mechanism and provide a basis for developing appropriate treatments.
