Role of Cocaine in Neuro-AIDS by HIV 1B and C Clades

描述（由申请人提供）：在美国和西方世界发现的主要HIV-1亚型是进化支B，这与存在于撒哈拉以南非洲和亚洲的进化支C有很大不同。据估计，在约4600万艾滋病毒-1感染者中，超过56%的感染者仅感染C支，艾滋病毒-1感染正在迅速蔓延到世界其他地区。艾滋病常伴有神经病理异常。可卡因是美国最广泛滥用的药物之一。目前对HIV-1神经发病机制或可卡因作用的理解来自美国和西方国家的B支，没有关于可卡因在C支神经发病机制中的相互作用的信息。我们假设进化支B和C对中枢神经系统细胞产生不同的影响，导致不同的神经发病机制，可卡因加剧了这些影响，其机制可能是通过丝裂原活化蛋白（MAP）激酶信号转导途径的失调介导的。因此，我们将首次研究（Aim #1a）在存在或不存在可卡因的情况下，B支和C支病毒体外感染对原代单核细胞和中枢神经系统细胞（星形胶质细胞、神经元、小胶质细胞）的促炎细胞因子（TNF1和il -6）、趋化因子（mcp -1和RANTES）和神经毒素（IDO）的产生和基因表达的影响。以及：（Aim #1b）分化失调的机制是否通过调节丝裂原活化蛋白（MAP）激酶信号转导途径介导。此外，这些体外感染研究将与离体研究（目标2）进行比较、关联和补充，离体研究使用来自迈阿密正在研究的使用和不使用可卡因的初发HIV-1B感染受试者的单核细胞，以及在印度合作研究所正在研究使用可卡因和不使用HIV-1C感染受试者的单核细胞。这些研究的结果可能a)有助于开发治疗上有用的药物或制剂，以减轻或预防与进化支特异性HIV-1感染和可卡因使用相关的神经发病机制；b)设计新的战略，以开发预防性和治疗性全球疫苗，诱导针对多进化支或重组大流行性HIV-1感染的跨进化支抗病毒免疫反应，这些感染目前正面临着包括美国在内的非b亚型世界最近在移徙人口和我国军人中都有报告。这一应用与PA-07-307的目的有重要的相关性。本项目将首次通过体外和离体模型系统研究可卡因对HIV-1B和HIV-C感染中神经致病分子的产生和基因表达的相互作用。确定进化支特异性神经发病机制将有助于设计新的策略，在使用药物和不使用药物的艾滋病毒感染受试者中开发预防性和治疗性全球疫苗，这些疫苗可以诱导跨进化的抗病毒免疫反应，以对抗包括美国在内的世界目前面临的多进化支或重组大流行性艾滋病毒1感染。

DESCRIPTION (provided by applicant): The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 46 million people infected with HIV-1, more than 56 % of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Cocaine is one of the most widely abused drugs in the U.S. Current understandings of HIV-1 neuropathogenesis or the role of cocaine emanate from B clade from U.S. and Western countries and no information is available on the interactive role of cocaine on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and cocaine exacerbates these effects and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study (Aim #1a) for the first time the effects of in vitro infection with clade B and C virus in presence or absence of cocaine on production and gene expression of pro-inflammatory cytokines, (TNF1 &IL-6), chemokines (MCP-1& RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, neurons, microglial cells), and whether :(Aim #1b) the mechanism of differential dysregulation is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from naive HIV-1B infected subjects who are using and non using cocaine being studied in Miami and cocaine using and non using HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) help to develop therapeutically useful drugs or agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and cocaine use and b) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals. PUBLIC HEALTH RELEVANCE This application has significant relevance to the purpose of the PA-07-307.This project will study for the first time the interactive role of cocaine on production and gene expression of neuropathogenic molecules in HIV-1B and HIV-C infection by both in vitro and ex vivo model system. Identification of the mechanism of clade specific neuropathogenesis will help to design novel strategies to develop preventive and therapeutic global vaccines in drug using and non-using HIV infected subjects that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.