Neuropathogenesis and Neuroinvasiveness of Subtype C Human Immunodeficiency Virus

描述（由申请人提供）：目前有3000多万人感染艾滋病毒，其中三分之二以上居住在撒哈拉以南非洲。尽管有许多预防方案，但每年仍有200多万新感染病例。在新感染病例中，增长最快、传播最快的亚型是HIV-1亚型C。这种亚型在亚洲和非洲等地区最为普遍，因为这些地区贫困人口占多数，艾滋病毒感染率高。现在有越来越多的证据表明，不同亚型之间存在差异，如亚型C，在疾病表现和发病机制。然而，对C亚型HIV-1的神经学表现、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的避难所也不清楚。从我们最近在赞比亚研究C亚型艾滋病毒/艾滋病神经发病机制的R21试点项目中获得的初步数据表明，运动功能和某些行为任务中的神经认知障碍可以通过抗逆转录病毒疗法逆转。有大量的脑膜炎，淋巴细胞浸润和神经炎症。机会性感染，特别是结核分枝杆菌的高频率，被发现。因此，C亚型HIV-1感染在神经组织病理学水平的影响需要进一步研究。本研究的总体目标是确定HIV-1C亚型神经致病性和病毒侵袭性的作用和可能机制，以及ART的作用。这将通过三个具体目标来实现：1）确定在以C亚型HIV-1为主的人群中，神经致病性和病毒侵袭性是否与AIDS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相关神经病理学的影响，HIV病毒载量和大脑是否可以作为病毒区室化和持续感染的储存库。鉴于C亚型HIV感染的优势和全球抗病毒治疗的规模扩大，更好地了解C亚型HIV的神经发病机制将对感染个体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亚型HIV感染和耐药性的影响尚未完全了解时。我们的研究还将导致更好的治疗方案，干预措施，并将导致新的预防策略的发展。

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.