Immuno-Neuropathogenic mechanisms of HIV-1 clade B and C Infection

描述（由申请人提供）： 全世界约有3 330万人感染了1型人类免疫缺陷病毒（HIV-1）。HIV-1显示出非凡的遗传变异，主要亚型，进化枝B，发现于北美、加拿大、巴西、西欧和澳大利亚，而进化枝C则特别发现于非洲、拉丁美洲、中国、印度和尼泊尔。其中，进化枝B和C代表了大部分（>86%）的循环HIV-1变体，并且超过56%的感染是进化枝C。艾滋病常伴有免疫和神经病理异常。多巴胺受体（DRD）和转运蛋白（DAT）在HIV感染的免疫神经发病机制中起重要作用。以往的研究表明，HIV-1的进化枝变异差异诱导的神经免疫致病机制。我们推测，进化枝B和C感染外周血来源的单核细胞和中枢神经系统（CNS）细胞产生差异的影响，导致差异的免疫神经病变的影响和机制可能是介导的钙调节失调？依赖性蛋白激酶（CaMK）信号通路。因此，我们将研究（目的#1）进化枝B和C病毒感染对单核细胞和原代人CNS细胞的多巴胺受体-2（DRD-2）、多巴胺转运蛋白（DAT）、限速酶酪氨酸羟化酶（TH）的基因表达和蛋白质修饰以及代谢产物高缬氨酸（HVA）水平的影响（星形胶质细胞，神经元，小胶质细胞），以及（目标#2）DRD-2和DAT的差异失调机制是否由Ca 2？依赖性蛋白激酶（CaMK）和元件结合蛋白（CREB）信号通路的cAMP应答。

DESCRIPTION (provided by applicant): Worldwide, approximately 33.3 million people are infected with human immunodeficiency virus type-1 (HIV-1). HIV-1 displays extraordinary genetic variations and the predominant subtype, clade B, is found in North America, Canada, Brazil, Western Europe and Australia whereas clade C is found specifically in Africa, Latin America, China, India and Nepal. Of these, clades B and C represent a large majority (>86%) of circulating HIV-1 variants and more than 56 % of the infection is with clade C. AIDS is often accompanied by immune and neuropathological abnormalities. Dopamine receptors (DRD) and transporter (DAT) are known to play a significant role in immuno-neuropathogenesis of HIV infection. Previous studies suggest that HIV-1 clade variations differentially induce the neuro-immunopathogenic mechanisms. We hypothesize that clade B and C infection exert differential effects on peripheral blood derived monocytes and central nerves system (CNS) cells leading to differential immuno-neuropathogenic effects and the mechanisms may be mediated by dysregulation of Ca2? dependent protein (CaMKs) kinases signaling pathways. Accordingly we will study (Aim #1) the effects of clade B and C virus infections on gene expression and protein modification of dopamine receptor-2 (DRD-2), dopamine transporter (DAT), rate limiting enzyme tyrosine hydroxylase (TH) and level of metabolite homovalinic acid (HVA) by monocytes and primary human CNS cells (astrocytes, neurons, microglial cells), and whether (Aim #2) the mechanism of differential dysregulation of DRD-2 and DAT is mediated by modulation of Ca2?dependent protein kinases (CaMKs) and cAMP response of element-binding protein (CREB) signaling pathways.