Mechanisms of 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3320万艾滋病毒-1感染者中，约60%的感染者仅感染C支，艾滋病毒- 1c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。目前对HIV-1神经发病机制的认识主要来自美国和西方国家的B支，而关于C支的神经发病机制的信息很少。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，其机制可能是由丝裂原活化蛋白（MAP）激酶信号转导通路失调介导的。因此，我们将首次研究（Aim #1a） 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、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，并检查（Aim #1b）。分支特异性病毒感染诱导的差异失调机制是否通过丝裂原活化蛋白（MAP）激酶信号转导途径的调节介导。此外，这些体外感染研究将与体外研究（目标2）进行比较、关联和补充，体外研究使用来自迈阿密研究的HIV-1B感染受试者和印度合作研究所研究的HIV-1C感染受试者的单核细胞。这些研究的结果可能a)揭示进化支特异性感染对神经发病机制的不同影响；b)帮助开发治疗上有用的药物，可以减轻或预防与进化支特异性HIV-1感染相关的神经发病机制；c)设计新的策略，开发预防和治疗性全球疫苗，可以诱导跨进化的抗病毒免疫反应，对抗多进化或重组大流行性HIV-1感染，目前面临的世界，包括美国，最近在移民人群和我们的人群中报道了非b亚型军事人员。

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.