Neuropathogenesis of clade C HIV in South Africa

描述（由申请人提供）：拟议的研究将利用圣路易斯密苏里州大学和南非开普敦大学之间的现有关系，以表征感染C型病毒的南非个体中HIV的神经行为特征。进化枝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型HIV的个体可能不太可能发展认知障碍，这是由于C型病毒中明显的达特蛋白（C31 S）的双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分支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，C支可能推断神经毒力，我们已经证明，在印度的C支病毒患者表现出认知障碍相对于血清阴性对照。最近，我们收集了来自南非一小群感染C分支的个体的数据，我们还获得了南非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，目前尚不清楚在进化枝C中鉴定的认知障碍是否存在于达特蛋白缺陷的背景下，或者它们是否与认知功能的其他已知病毒学相关物如前病毒DNA水平有关。此外，还没有研究涉及进化枝C HIV的神经影像学特征。在本研究中，我们将检查200名未经治疗的HIV阳性C支HIV患者和50名血清阴性的健康对照，这些对照与人口统计学特征相匹配，全部招募自南非。将从患者和对照组中获得实验室、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（Laidlaw）成员开发的定量纤维束成像的新指标，以及作为进化枝B HIV损伤的已知神经成像特征的传统体积指数。这将是第一个跨学科的研究进化枝C神经发病机制和结果将显着推进我们的理解病毒进化枝多样性和认知结果与艾滋病毒。公共卫生相关性：本研究的目的是确定C型HIV对南非个体认知功能的影响。我们的目的是证明，尽管存在达特蛋白缺陷，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水平和新的神经影像学特征的标志物相关。

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.