Role of Opioids and Complements in AIDS Pathogenesis

描述(由申请者提供)：这项建议是为了在天普大学神经病毒学中心获得三年指导研究奖，以促进艾滋病发病机制的职业发展。首席调查员将扩大他的技能，并在艾滋病领域的独立研究之前征求艾滋病研究和药物滥用领域的进一步培训。本研究的长期目标是明确补体系统在神经艾滋病和艾滋病发病机制中的调节机制(S)和作用，以及滥用药物的增强作用。HIV和HTLV在抵抗补体介导的病毒裂解方面是独一无二的。HIV特异性抗体增强补体成分C3和C5在病毒粒子上的活化和沉积，从而保护它们免受中和抗体的攻击，同时通过补体受体增强巨噬细胞的感染。鉴于这些特性，补体可以促进病毒的传播，在宿主内传播，并有助于逃避免疫系统。此外，HIV激活的补体蛋白具有促炎和趋化作用，与神经艾滋病和HIVAN的发病机制有关。抑制补体合成和激活可能是预防病毒诱导损伤的一个假定的治疗目标。我们的初步研究表明，炎性细胞因子、C/EBP-β和Delta激活C3启动子。过量表达显性负性p38pha或MKK6可减弱C3启动子的活性，而吗啡可刺激细胞因子诱导的C3表达。我们推测，阿片类药物可能通过上调MKK6和p38MAPK的活性来诱导C3的表达，进而调节C3启动子激活的关键角色C/EBP，从而在神经艾滋病和HIVAN的发病机制中发挥不利作用。这些研究将阐明宿主蛋白激活补体的分子机制，以及阿片类药物在体外细胞培养系统和恒河猴免疫缺陷病毒(SIV)感染模型中对补体激活的影响。杰伊·拉帕波特博士是一位神经艾滋病专家，他将指导PI的科学发展。为了加强培训，该项目将包括阿片受体生物学专家托马斯·J·罗杰斯博士。这些研究结果将有助于更好地理解HIV感染和药物滥用中补体介导的损伤机制，并为PI提供有效的培训/指导机制。

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.