Role of Opioids and Complements in AIDS Pathogenesis

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DESCRIPTION (provided by applicant): This proposal is for a three year mentored research award at the Center for Neurovirology, Temple University for the development of a career in AIDS pathogenesis. The principal investigator will expand upon his skills and solicits further training in field of AIDS research and drug abuse prior to independent research in the field of AIDS. The long-term goal of this research is to define the mechanism(s) of regulation and role of the complement system in the pathogenesis of neuroAIDS and HIVAN and the potentiating role of drugs of abuse. HIV and HTLV are unique in their resistance to complement mediated virolysis. HIV-specific antibodies augment both activation and deposition of complement components as C3 and C5 on virions thus protecting them from neutralizing antibodies and the same time enhance infection of macrophages through complement receptors. In view of these properties, complement may facilitate virus transmission, dissemination within the host, and contribute to evasion of immune system. Furthermore, complement proteins activated by HIV have pro-inflammatory and chemotactic properties relevant to the pathogenesis of both NeuroAIDS and HIVAN. Inhibition of complement synthesis and activation may represent a putative therapeutic goal to prevent virus-induced damage. Our preliminary studies indicate that inflammatory cytokines, and C/EBP-beta and delta activate C3 promoter. Overexpression of dominant negative p38alpha or MKK6 attenuates C3 promoter activity, while morphine stimulates cytokine induced C3 expression. We hypothesize that opiates may play a detrimental role in the pathogenesis of NeuroAIDS and HIVAN by inducing C3 expression via upregulation of MKK6 and p38 MAPK activity which in turn modulates C/EBP's, the critical player in C3 promoter activation. The proposed studies will elucidate the molecular mechanism of complement activation by host proteins, and the effects of opioids on complement activation in in vitro ceil culture systems and in a rhesus macaque model of simian immunodeficiency virus (SIV) infection. Dr. Jay Rappaport, an expert in NeuroAIDS, will mentor the Pi's scientific development. To enhance the training, the program will include Dr. Thomas J. Rogers, expert in opioid receptor biology. The results of these studies will facilitate a better understanding of the mechanisms of complement-mediated injury in HIV infection and drug abuse, and serve as an effective training/mentoring mechanism for the PI.