Central Nervous System Events in Primary HIV Infection

描述(申请人提供)：由于有效的抗逆转录病毒疗法(ART)，感染人类免疫缺陷病毒(HIV)的患者现在活得更长了。尽管抗逆转录病毒疗法对系统性病毒抑制有效，但多达一半的慢性艾滋病毒感染者(HIV+)将发展为艾滋病毒相关神经认知障碍(HAND)。越来越多的努力集中于了解在初次艾滋病毒感染(PHI，定义为艾滋病毒传播后的第一年)期间中枢神经系统(CNS)内的早期病理生理变化。目前尚不清楚在PHI期间早期开始抗逆转录病毒治疗是否可以减少未来发生手部疾病的几率。开发早期生物标志物(包括脑脊液和神经成像)以了解可能影响中枢神经系统损伤轨迹的关键早期事件的机制是势在必行的。以前对PHI的研究主要是横断面的，集中在有限数量的PHI参与者身上，通过单一的方式进行评估。我们建议进行一项纵向研究，以评估PHI和早期ART对脑结构的影响，该研究将结构性神经成像分析与血液和脑脊液感染、炎症和神经去核的测量以及临床数据(包括暴露于滥用的刺激性药物)相结合，以探讨在PHI期间开始脑损伤的可能机制。具体地说，这项研究将使用结构神经成像方法(扩散张量成像(DTI)和脑体积计量学)来研究中枢神经系统PHI自然病程的中枢机制，以及在感染早期启动ART的效果。基于我们的初步横断面分析，我们假设结构神经成像(DTI和脑体积计量学)将在ART之前的早期感染期间揭示大脑的进行性损伤，在血清转换后不久启动ART的受试者中可能停止这种损伤。使用甲基苯丙胺的受试者可能会增加对艾滋病毒相关结构性损伤的易感性，这与大脑中的炎症有关。这一建议将：(目的1)通过将结构成像异常的出现与实验室生物标记物和神经心理表现暂时联系起来，在抗逆转录病毒治疗前研究PHI的中枢神经系统损伤的机制。此外(目标2)我们将通过评估受试者在开始抗逆转录病毒治疗前后的脑白质完整性和脑容量随时间的变化，来探索早期抗逆转录病毒治疗在中枢神经系统的作用机制。我们的长期目标是为ART启动的适当时机提供证据，并评估可能的定制辅助神经保护疗法预防手部疾病的理论基础。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infected patients are now living longer due to potent antiretroviral therapy (ART). Despite the effectiveness of ART for systemic viral suppression, up to half of chronically HIV infected (HIV+) individuals will develop HIV associated neurocognitive disorders (HAND). Increasing efforts have focused on understanding the early pathophysiologic changes within the central nervous system (CNS) initiated during primary HIV infection (PHI, defined as the first year after HIV transmission). It remains unknown if early initiation of ART during PHI could reduce the future incidence of developing HAND. It is imperative that early biomarkers (including cerebrospinal fluid (CSF) and neuroimaging) are developed for understanding the mechanisms of crucial early events that may influence the trajectory of damage in the CNS. Previous studies of PHI have primarily been cross sectional and have focused on a limited number of PHI participants assessed by single modality. We propose a longitudinal study to assess the effects of PHI and early ART on brain structure which integrates structural neuroimaging analyses with blood and CSF measures of infection, inflammation and neurodenegeration, as well as clinical data including exposure to stimulant drugs of abuse to investigate possible mechanisms of brain injury beginning during PHI. Specifically, this study will employ structural neuroimaging methods (diffusion tensor imaging (DTI) and brain volumetrics) to study the CNS mechanisms that underlie the natural history of PHI in the CNS as well as the effects of starting ART in the early stages of infection. Based on our preliminary cross sectional analyses, we hypothesize that structural neuroimaging (DTI and brain volumetrics) will reveal progressive injury in the brain during early infection prior to ART which may be halted in subjects that initiate ART soon after seroconversion. Subjects using methamphetamine may have increased vulnerability to HIV-associated structural injury, tied to inflammation in the brain. This proposal will: (Aim 1) investigate the mechanisms of CNS injury in PHI prior to ART by temporally associating the emergence of abnormalities in structural imaging with laboratory biomarkers and neuropsychological performance. Additionally (Aim 2) we will explore the mechanisms of early ART effects in the CNS through assessment of white matter integrity and brain volumetrics over time in subjects both before and after starting ART. Our long term goal is to provide evidence for the appropriate timing of ART initiation and to evaluate the rationale of possible tailored adjunctive neuroprotective therapies to prevent HAND.