Mechanisms of Neuro-AIDS by HIV 1B and C Clades

描述(申请人提供)：在美国和西方世界发现的主要HIV-1亚型是B分支，它与存在于撒哈拉以南非洲和亚洲的C分支有很大不同。据估计，在约3320万感染HIV-1的人中，约60%的感染者仅感染C类病毒，而HIV-1C病毒感染正在迅速蔓延至世界其他地区。艾滋病常伴有神经病理异常。目前对HIV-1神经发病机制的认识源于美国和西方国家的B分支，对C分支神经发病机制的了解很少。我们推测B分支和C分支对中枢神经系统细胞具有不同的作用，导致不同的神经发病机制，其机制可能是通过丝裂原活化蛋白(MAP)激酶信号转导通路的失调而介导的。因此，我们将首次研究：(目的#1a)体外感染B和C分支病毒对原代单核细胞和中枢神经系统细胞(星形胶质细胞、小胶质细胞)产生和表达致炎细胞因子(TNF1和IL-6)、趋化因子(MCP-1和RANTES)和神经毒素(IDO)的影响，并研究(目的#1b)分支特异性病毒感染导致差异调节失调的机制是否通过调节丝裂原激活蛋白(MAP)信号转导通路而介导。此外，这些体外感染研究将与在迈阿密研究的HIV-1B感染者的单核细胞和在印度合作研究所研究的HIV-1C感染者的单核细胞的体外研究(AIM#2)相比较、相互关联和补充。这些研究得出的结果可能如下：a)揭示特定分支感染对神经发病的不同影响；b)有助于开发治疗有用的药物，以减轻或预防与特定分支HIV-1感染相关的神经发病；以及c)设计新的策略，以开发能够诱导针对目前世界各地面临的多分支或重组大流行HIV-1感染的跨分支抗病毒免疫反应的新型全球疫苗，其中包括美国，在美国，最近有报告在流动人口和我国军人中发现了非B亚型。

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 33.2 million people infected with HIV-1, about 60% 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. Current understandings of HIV-1 neuropathogenesis emanate from B clade from U.S and Western countries and very little information is available on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study for the first time :(Aim #1a) the effects of in vitro infection with clade B and C virus 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, microglial cells) and examine (Aim #1b), whether the mechanism of differential dysregulation induced by clade specific virus infection 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 HIV-1B infected subjects being studied in Miami and HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) unravel the differential effect of clade specific infection on neuropathogenesis, b) help to develop therapeutically useful agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and c) 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.