Neuropathogenesis and Neuroinvasiveness of Subtype C Human Immunodeficiency Virus

C亚型人类免疫缺陷病毒的神经发病机制和神经侵袭性

• 批准号: 8470732
• 负责人: Charles Wood
• 金额: $ 33.11万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470732
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Africa; Africa South of the Sahara; African; Anti-Retroviral Agents; Asia; Autopsy; Behavioral; Blood; Brain; Correlation Studies; Country; Data; Developing Countries; Development; Disease; Disease Management; Disease Progression; Drug resistance; Effectiveness; Frequencies; Genotype; Goals; HIV; HIV Infections; HIV-1; Impairment; Individual; Infection; Infiltration; Intervention; Lead; Lymphocyte; Meningitis; Motor; Mycobacterium tuberculosis; Neuraxis; Neurocognitive; Neurologic Dysfunctions; Neurologic Manifestations; Neuropathogenesis; Opportunistic Infections; Pathogenesis; Pilot Projects; Play; Population; Poverty; Prevention program; Prevention strategy; Recruitment Activity; Research; Research Infrastructure; Resistance to infection; Role; Site; Specimen; Staging; Treatment Protocols; Viral; Viral Load result; Virus; Virus Diseases; Work; Zambia; antiretroviral therapy; brain tissue; cohort; fungus; neuroinflammation; neuropathology; novel; prevent; pyrosequencing; response; scale up

DESCRIPTION (provided by applicant): Over 30 million people are currently infected by HIV and over two thirds of them currently reside in sub- Saharan Africa. There are still over 2 million new infections occurring annually in spite of numerous prevention programs. Of the new infections, the fastest growing and most rapidly spreading subtype is HIV-1 subtype C. This subtype is most prevalent in regions such as Asia and Africa where a preponderance of poverty and high HIV infection rates co-exist. There are now growing evidence that there are differences among different subtypes, such as subtype C, in disease manifestation and pathogenesis. However, little is known about the neurological manifestation, neuropathogenesis, and neuroinvasiveness of subtype C HIV-1, and whether the central nervous system can be a sanctuary for subtype C HIV-1 is not known. Preliminary data derived from our recent R21 pilot project to study subtype C HIV/AIDS neuropathogenesis in Zambia have shown that neurocognitive impairment in motor functions and certain behavioral tasks could be reversed by anti-retroviral therapy (ART). There were substantial levels of meningitis, lymphocyte infiltration and neuroinflammation. A high frequency of opportunistic infection, especially mycobacterium tuberculosis, was detected. Therefore, the effects of subtype C HIV-1 infection at the neurohistopathological level needs to be further investigated. The overall goal of this proposal is to determine the effects and possible mechanism of HIV-1 subtype C neuropathogenesis and viral invasiveness, and the effect of ART. This will be accomplished with three specific aims: 1) To determine whether neuropathogenesis and viral neuroivasiveness are related to the AIDS disease progression in a predominately subtype C HIV-1 population; 2) To determine the role of opportunistic infection and HIV-1 in the development of neuropathology and their correlation with HIV disease progression; 3) To determine the effect of ART on subtype C HIV associated neuropathology, HIV viral load and whether the brain can serve as a reservoir for viral compartmentalization and persistent infection. Given the predominance of subtype C HIV infection and the scale up of anti-viral therapy globally, a better understanding of subtype C HIV neuropathogenesis will have substantial impact on both disease management and the use of anti-retroviral therapy in infected individuals, especially when the effects of ART on subtype C HIV infection and drug resistance is not fully understood. Our study will also lead to better treatment regimens, interventions, and will lead to the development of novel preventive strategies.

描述（由申请人提供）：目前有超过 3000 万人感染艾滋病毒，其中三分之二以上目前居住在撒哈拉以南非洲地区。尽管采取了许多预防计划，但每年仍有超过 200 万例新感染病例发生。在新感染病例中，增长最快、传播最迅速的亚型是 HIV-1 C 亚型。该亚型在亚洲和非洲等贫困和艾滋病毒高感染率并存的地区最为流行。现在越来越多的证据表明不同亚型（例如C亚型）之间的疾病表现和发病机制存在差异。然而，人们对C亚型HIV-1的神经表现、神经发病机制和神经侵袭性知之甚少，中枢神经系统是否可以成为C亚型HIV-1的庇护所也不得而知。我们最近在赞比亚研究 C 亚型 HIV/艾滋病神经发病机制的 R21 试点项目得出的初步数据表明，运动功能和某些行为任务的神经认知损伤可以通过抗逆转录病毒治疗 (ART) 来逆转。存在大量脑膜炎、淋巴细胞浸润和神经炎症。检测到高频率的机会性感染，尤其是结核分枝杆菌。因此，C亚型HIV-1感染在神经组织病理学水平上的影响需要进一步研究。该提案的总体目标是确定 HIV-1 C 亚型神经发病机制和病毒侵袭性的影响和可能机制，以及 ART 的效果。这将通过三个具体目标来实现：1）确定神经发病机制和病毒神经血管性是否与主要是 C 亚型 HIV-1 人群中的艾滋病疾病进展有关； 2) 确定机会性感染和HIV-1在神经病理学发展中的作用及其与HIV疾病进展的相关性； 3) 确定 ART 对 C 亚型 HIV 相关神经病理学、HIV 病毒载量以及大脑是否可以作为病毒区室化和持续感染的储存库的影响。鉴于 C 型 HIV 感染占主导地位以及全球范围内抗病毒治疗的扩大，更好地了解 C 型 HIV 神经发病机制将对感染者的疾病管理和抗逆转录病毒治疗的使用产生重大影响，特别是当ART 对 C 型 HIV 感染和耐药性的影响尚不完全清楚。我们的研究还将带来更好的治疗方案、干预措施，并将导致新的预防策略的发展。