Neuropathogenesis and Neuroinvasiveness of Subtype C Human Immunodeficiency Virus

说明（由申请人提供）：目前有3 000多万人感染艾滋病毒，其中三分之二以上目前居住在撒哈拉以南非洲。尽管有许多预防方案，每年仍有200多万新感染病例。在新感染中，增长最快和传播最迅速的亚型是艾滋病毒1亚型c。这种亚型在亚洲和非洲等地区最为普遍，这些地区普遍存在贫困和高艾滋病毒感染率。现在越来越多的证据表明，不同亚型之间在疾病表现和发病机制上存在差异，如C亚型。然而，关于C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型HIV-1的避难所尚不清楚。我们最近在赞比亚研究C亚型HIV/AIDS神经发病机制的R21试点项目的初步数据表明，运动功能和某些行为任务的神经认知障碍可以通过抗逆转录病毒治疗（ART）逆转。有大量的脑膜炎、淋巴细胞浸润和神经炎症。机会性感染的发生率较高，尤其是结核分枝杆菌感染。因此，C亚型HIV-1感染在神经组织病理学水平的影响有待进一步研究。本提案的总体目标是确定HIV-1亚型C神经发病机制和病毒侵袭性的作用和可能的机制，以及ART的作用。这将有三个具体目的：1)确定在主要的C亚型HIV-1人群中，神经发病机制和病毒神经侵袭性是否与艾滋病疾病进展有关；2)确定机会性感染和HIV-1在神经病理发生中的作用及其与HIV疾病进展的相关性；3)确定ART对C型HIV相关神经病理学、HIV病毒载量的影响，以及大脑是否可以作为病毒区隔化和持续感染的储存库。鉴于C型HIV感染的优势和全球抗病毒治疗的规模，更好地了解C型HIV神经发病机制将对疾病管理和感染者抗逆转录病毒治疗的使用产生重大影响，特别是在抗逆转录病毒治疗对C型HIV感染和耐药性的影响尚未完全了解的情况下。我们的研究也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. PUBLIC HEALTH RELEVANCE: Over half of the global new HIV-1 infection is by the subtype C virus, which is predominant in sub-Saharan African. Very little is known about the neurological dysfunction of individuals infected by this group of viruses, and whether they are even neuroinvasive is controversial. Our preliminary results from a Zambian cohort showed that subtype C infected individuals have substantial neuropathology and opportunistic infections in the brain. We are now proposing to further study the correlation between subtype C infection of the brain, opportunistic infections and disease progression. This study will lead a better understanding of HIV neuropathogenesis and development of strategies to prevent the disease.