HIV-1 Clade Diversity and Macrophage Mediated Neurotoxicity in HIV-1 Dementia

描述（由申请人提供）：HIV-1进化枝C目前负责超过50%的新的HIV感染，现在是全球最常见的传播亚型。虽然HIV-1相关性痴呆（HAD）仍然是美国和欧洲B支感染者中艾滋病的主要神经病理学表现，但在印度和撒哈拉以南非洲等C支感染流行的地区，HAD的发病率似乎较低。目前尚不清楚神经艾滋病的低明显患病率是由于艾滋病毒分支发病机制的潜在差异，还是仅仅是数据采样、临床诊断或机会性感染等混杂变量的人为因素。进化枝B和C神经毒力的潜在差异以及HIV-1感染的脑单核吞噬细胞（MP;血管周围巨噬细胞和小胶质细胞）介导发病机制的机制还有待研究。我们最近的初步数据表明，在HIV-1感染期间，进化枝B病毒株可能比进化枝C病毒株产生更多的神经毒素，如谷氨酸。我们先前已经表明，MP的HIV-1进化枝B感染通过酶谷氨酰胺酶导致谷氨酸产生增强。在这个R21应用中，我们假设神经毒性是通过脑炎症和HIV-1感染的巨噬细胞中转氨酶的失调介导的。与HIV进化枝B相比，我们假设进化枝C分离株将表现出感染效率降低、细胞因子/趋化因子谱改变以及受感染MP的谷氨酸产生减少，从而为进化枝B和C感染脑之间的差异提供了机制性见解。我们将应用由一组HIV-1毒株（HIV-1实验室进化枝B毒株、初级进化枝B毒株和初级进化枝C毒株）感染的人单核细胞衍生的巨噬细胞（MDM）至严重联合免疫缺陷（SCID）HIV-1脑炎（HIVE）小鼠模型，从而在体内模拟巨噬细胞驱动的HAD。该方法将利用模拟HIV-1感染和脑MP免疫激活的实验室测定来研究CNS免疫应答对炎症因子和神经毒素产生的影响以及HAD期间发生的神经元损伤。这项应用将建立一个工作的基础，详细说明病毒分支之间的差异和对艾滋病毒引起的大脑炎症和痴呆症的潜在影响。确定HIV-1感染的MP和细胞因子影响神经元损伤的机制可能会发现治疗HAD和其他神经退行性疾病的新治疗策略。HIV-1病毒株C进化枝目前负责超过50%的新的HIV感染，现在是全球最常见的传播亚型。虽然HIV-1相关性痴呆仍然是美国和欧洲HIV-1进化枝B感染者中艾滋病的主要神经系统并发症，但在印度和撒哈拉以南非洲等地区，HIV-1相关性痴呆的发病率似乎较低。这项应用将建立一个工作的基础，详细说明病毒进化枝B和C之间的差异和对艾滋病毒引起的痴呆症的潜在影响。我们希望，确定HIV-1影响神经元损伤的机制可能会发现治疗HIV-1相关痴呆和其他神经退行性疾病的新治疗策略。

DESCRIPTION (provided by applicant): HIV-1 clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia (HAD) continues to be a major neuropathological manifestation of AIDS among clade B-infected individuals in the US and Europe, the incidence of HAD in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. Whether the low apparent prevalence of neuroAIDS is due to underlying differences in HIV-clade pathogenesis or simply an artifact of confounding variables such as data sampling, clinical diagnosis or opportunistic infections is unclear. Potential differences in clade B and C neurovirulence and the mechanism by which HIV-1 infected brain mononuclear phagocytes (MP; perivascular macrophages and microglia) mediate pathogenesis have yet to be investigated. Our recent preliminary data indicates clade B viral strains may produce more neurotoxins, such as glutamate, during HIV-1 infection than clade C viral strains. We have shown previously that HIV-1 clade B infection of MP leads to enhanced glutamate production through the enzyme glutaminase. In this R21 application, we hypothesize that neurotoxicity is mediated through brain inflammation and the dysregulation of glutaminase in HIV-1-infected macrophages. In comparison to HIV clade B, we hypothesize clade C isolates will demonstrate decreased infection efficiency, altered cytokine/chemokine profiles, and decreased glutamate production by infected MP, providing mechanistic insight into differences between clade B and C infection of the brain. We will apply human monocyte-derived macrophage (MDM) infected by a panel of HIV-1 strains (HIV-1 laboratory clade B strains, primary clade B strains and primary clade C strains), to a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, thus modeling macrophage driven HAD in vivo. This approach will utilize laboratory assays that mimic HIV-1 infection and immune activation of brain MP to investigate the effects of the CNS immune response on production of inflammatory factors and neurotoxins as well as neuronal injury as it occurs during HAD. This application will establish a foundation of work detailing the differences between viral clades and the potential implications for HIV-induced brain inflammation and dementia. Determining the mechanisms by which HIV-1 infected MP and cytokines influence neuronal injury may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. HIV-1 viral strain clade C is currently responsible for more than 50% of new HIV infections and is now the most commonly transmitted subtype worldwide. While HIV-1-associated dementia continues to be a major neurological complication of AIDS among HIV-1 clade B-infected individuals in the US and Europe, the incidence of HIV-1-associated dementia in regions like India and sub-Saharan Africa, where clade C infection is prevalent, appears to be lower. This application will establish a foundation of work detailing the differences between viral clade B and C and the potential implications for HIV-induced dementia. It is our hope that determining the mechanisms by which HIV-1 influence neuronal injury may identify new therapeutic strategies for treating HIV-1-associated dementia and other neurodegenerative disorders.