Neuropathogenesis of clade C HIV in South Africa

描述(由申请人提供)：这项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来表征感染C分支病毒的南非人中艾滋病毒的神经行为特征。分支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。早期的研究表明，感染C分支HIV的个体可能不太可能出现认知障碍，这是由于C分支病毒中明显的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，最近在埃塞俄比亚对感染C分支病毒的人进行的一项研究显示出轻微的认知损害。然而，其他生物学研究表明，分支C可能推断出神经毒力，我们已经证明，印度的分支C病毒患者相对于血清阴性对照表现出认知障碍。最近，我们收集了南非感染C分支的一小群人的数据，我们还获得了南非艾滋病毒患者的神经成像。这些初步研究表明，居住在南非的C级患者的认知可能会受到负面影响。然而，尚不清楚在C分支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与认知功能相关的病毒学相关，如前病毒DNA水平。此外，还没有研究涉及C类艾滋病毒的神经成像特征。在这项研究中，我们将检查200名接受治疗的未接受治疗的艾滋病毒阳性患者和50名血清阴性的健康对照，这些人都是从南非招募的，与人口统计特征相匹配。实验室、认知和神经成像数据将从患者和对照组获得。神经成像将包括扩散张量成像(DTI)，以得出我们团队(Laidlaw)成员开发的量化气管造影术的新指标，以及已知的B分支HIV受损的神经肿瘤特征的传统体积指数。这将是对C分支神经发病机制的第一次跨学科研究，其结果将极大地促进我们对病毒分支多样性和与艾滋病毒相关的认知结果的理解。公共卫生相关性：这项研究的目的是确定C分支艾滋病毒对南非个人认知功能的影响。我们的目标是证明，尽管存在TAT蛋白缺陷，但感染C分支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的标记物相关。

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.