Neuropathogenesis of clade C HIV in South Africa

描述（由申请人提供）：拟议的研究将利用密苏里大学圣路易斯分校和南非开普敦大学之间的现有关系，表征南非C支病毒感染个体的HIV神经行为特征。进化支C代表了世界上最常见的艾滋病毒形式，它仍然是南非的主要毒株。早期研究表明，感染C支HIV的个体可能不太可能发生认知障碍，这是由于C支病毒中Tat蛋白（C31S）的二半胱氨酸基序的自然变异。为了支持这一假设，最近对埃塞俄比亚感染C枝病毒的个体进行的一项研究显示出最小的认知障碍。然而，其他生物学研究表明，进化枝C可能推断神经毒性，我们已经证明，在印度，与血清阴性对照相比，进化枝C病毒患者表现出认知障碍。最近我们在南非收集了一小群感染C支的个体的数据，我们也获得了南非HIV患者的神经成像。这些初步研究表明，居住在南非的C支患者的认知可能受到负面影响。然而，尚不清楚在进化支C中发现的认知障碍是否存在于Tat蛋白缺陷的背景下，或者它们是否与其他已知的认知功能病毒学相关因素（如原病毒DNA水平）有关。此外，还没有研究涉及C支HIV的神经影像学特征。在本研究中，我们将检查200名未接受治疗的HIV阳性的C支HIV患者和50名人口统计学特征匹配的血清阴性健康对照者，这些患者均来自南非。将从患者和对照组获得实验室、认知和神经影像学数据。神经成像将包括扩散张量成像（DTI），以获得由我们的团队成员（Laidlaw）开发的量化神经束造影的新指标，以及传统的体积指标，这些指标是已知的B支HIV损伤的神经成像特征。这将是首个关于C支神经发病机制的跨学科研究，其结果将显著促进我们对病毒分支多样性和与HIV相关的认知结果的理解。公共卫生相关性：本研究的目的是确定C支HIV对南非个体认知功能的影响。我们的目的是证明，尽管存在Tat蛋白缺陷，但在感染进化支C的个体中存在认知障碍。我们还旨在证明这些损伤与前病毒DNA水平和新的神经成像特征标志物相关。

DESCRIPTION (provided by applicant): The proposed study will capitalize on existing relationships between the University of Missouri, St. Louis, and the University of Cape Town, South Africa to characterize the neurobehavioral signatures of HIV in South African individuals infected with clade C virus. Clade C represents the most common form of HIV in the world and it remains a dominant strain in South Africa. Early studies suggested that individuals infected with clade C HIV may be less likely to develop cognitive impairments due to a natural variation in the dicysteine motif of the Tat protein (C31S) evident in clade C virus. In support of this hypothesis a recent study of individuals infected with clade C virus in Ethiopia exhibited minimal cognitive impairment. However, other biological studies suggest that clade C may infer neurovirulence and we have demonstrated that patients with clade C virus in India exhibit cognitive impairment relative to seronegative controls. Recently we have collected data from a small group of individuals infected with clade C in South Africa, and we also have obtained neuroimaging on HIV patients in South Africa. These preliminary studies suggest that cognition is likely negatively affected in clade C patients residing in South Africa. However, it is unknown whether the cognitive impairments identified in clade C are present in the context of the Tat protein defect, or whether they relate to other known virologic correlates of cognitive function such as proviral DNA level. Further, no study has addressed the neuroimaging signatures of clade C HIV. In the present study we will examine 200 treatment-naive, HIV-positive individuals with clade C HIV and 50 seronegative healthy controls matched on demographic characteristics and all recruited from South Africa. Laboratory, cognitive, and neuroimaging data will be obtained from the patients and controls. Neuroimaging will consist of diffusion tensor imaging (DTI) to derive novel metrics of quantified tractography developed by members of our team (Laidlaw) as well as traditional volumetric indices that are known neuriomaging signatures of impairment in clade B HIV. This will be the first transdisciplinary study of clade C neuropathogenesis and the results will significantly advance our understanding of viral clade diversity and cognitive outcomes associated with HIV. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the impact of clade C HIV on cognitive function among individuals in South Africa. We aim to demonstrate that cognitive impairment is present among individuals infected with clade C despite the presence a Tat protein defect. We also aim to demonstrate that these impairments correlate with proviral DNA levels and markers of novel neuroimaging signatures.