In the decade since the introduction of highly affective anti-retroviral therapy (HAART), the severity of the clinical course of AIDS has been ameliorated for a majority of afflicted individuals in most developed societies. However, in the developing world the incidence and clinical severity of AIDS continues in an exponential fashion fueled, in part, by inadvertent HIV-1 exposure through intravenous drug use. In an existing NIDA-supported Program Project at the Scripps Research Institute (DA12444), I direct a series of studies employing several animal models of neuroAIDS that investigate the potential toxic interaction between viral-induced neuropathogenesis and drugs of abuse. We now have strong evidence of a positive interaction, i.e. synergy, between methamphetamine-induced toxicity and the progression of NeuroAIDS in these animal models. The mechanisms underlying this synergy are not apparent but may, in part, involve interactions of directly toxic viral products (i.e. gp120) with host-derived factors targeting neurons and/or glib, and with compromised cellular processes precipitated by drug-related oxidative stress and loss of redox poise. In this CEBRA application we propose to initiate a new series of studies that will conceptually extend the current line of investigation that could better elucidate the cellular and molecular mechanisms that lead to the toxic synergism between viral products, host-derived factors and drugs of abuse. The proposed research plan involves a very new chemical approach that utilizes a novel form of proteomic analysis in which the activation state of specific proteins (enzymes) will be characterized and quantified in two accepted animal models of AIDS-related neuropathogenesis in the context of methamphetamine exposure. These new methods, pioneered at The Scripps Research Institute, take advantage of the fact that activation states of specific enzyme families are a more accurate reflection of the functional state of proteins than are protein levels per se. Genetically engineered mice over-expressing either the HIV-1 viral coat protein, gp120, or the host-derived, immune-related cytokine, IL-6, in astrocytes, will be used to compare and contrast the activity states of enzymes involved in these two independent models of AIDS-related neuropathogenesis. These studies will comprise the first proteome activity analysis of these of neuroAIDS models, and will provide a unique molecular profile of the neurotoxic synergy elicited by methamphetamine.
