Monocytes and HIV CNS Reservoirs in Super Acute HIV Infection

描述（由申请人提供）：本研究旨在确定急性HIV感染（AHI）期间单核细胞/巨噬细胞（MO）表型和功能的早期变化，并确定早期开始联合抗逆转录病毒治疗（cART）的时机在预防长期HIV诱导的MO特征改变和MO的HIV感染中的作用。在初始暴露于HIV的背景下，HIV建立了中枢神经系统（CNS）感染库。提出的目标将表征持久性艾滋病毒储存库，这可能有助于我们理解开发治疗HIV-1感染的创新策略。MO特征的变化和MO艾滋病毒负担的程度与神经认知障碍（NCI）的发展密切相关。由于涉及受干扰的MO人群的脑损伤可能在暴露于HIV后很早就发生，因此了解HIV感染早期MO扰动的自然历史对于根除HIV和制定干预概念至关重要。单核细胞稳态的改变在慢性HIV中具有深远的临床意义，我们的实验室最近发现了慢性HIV中MO的表型和功能紊乱，这有助于NCI，并证明MO具有与NCI相关的高HIV负担。与美国国立卫生研究院资助的RV254/SEARCH 010队列的研究人员合作，在泰国曼谷有超过100例AHI病例，拟议的研究提供了一个独特的机会，通过利用标本和生物测量，包括脑脊液（CSF）炎症评估和脑磁共振波谱（MRS），来定义AHI期间单核细胞的最早变化。我们已经确定了感染的时间，从HIV暴露开始平均2周，并确定了全身和脑脊液细胞反应和HIV病毒负担的模式。我们建议定义AHI中MO特征和病毒负担上升到类似慢性感染的高水平的最早时间点，并将其与(1)早期神经侵袭联系起来，其特征是可测量的中枢神经系统炎症循环标志物和MRS检测到的脑实质炎症；(2)通过CSF/血浆HIV病毒载量比评估基线病毒渗透；(3)评估早期抑郁性cART和替米沙坦+ cART强化治疗对MO炎症的影响。

DESCRIPTION (provided by applicant): This proposal seeks to define early changes to monocyte/macrophages (MO) phenotype and function induced during acute HIV infection (AHI) and to determine the role of timing of early initiation of combination antiretroviral therapy (cART in preventing long term HIV-induced alterations on MO profile and HIV infection of MO. In the context of initial exposure to HIV which establishes the central nervous system (CNS) reservoir of infection, the proposed aims will characterize persistent HIV reservoirs which could contribute to our understanding to develop innovative strategies to cure the body of HIV-1 infection. Changes to MO profile and the degree of MO HIV burden are closely linked to development of neurocognitive impairment (NCI). Because brain injury involving perturbed MO populations may occur very early upon exposure to HIV, understanding the natural history of MO perturbations in the earliest stages of HIV infection is critical to eradicating HIV and strategizing concepts of intervention. Alterations in monocyte homeostasis have profound clinical implications in chronic HIV and our lab has recently identified a perturbed phenotypic and functional MO profiles in chronic HIV that contributes to NCI as well as demonstrated that MO harbor high HIV burden that is associated with NCI. In collaboration with investigators of the NIH-funded RV254/SEARCH 010 cohort with over 100 AHI cases in Bangkok, Thailand, the proposed study presents a unique opportunity to define the earliest changes to monocytes during AHI by leveraging specimens and biological measurements including cerebrospinal fluid (CSF) inflammatory assessments and magnetic resonance spectroscopy (MRS) of the brain. We have established the timing of infection on average 2 weeks from onset of HIV exposure and defined the pattern of systemic and CSF cellular responses and HIV viral burden. We propose to define the earliest timepoint in AHI where MO features and viral burden rise to high levels resembling chronic infection and relate this to (1) early neuroinvasion that will be characterized by measurable circulating markers of CNS inflammation and by brain parenchymal inflammation as detected by MRS, (2) baseline viral penetration assessed by CSF/Plasma HIV viral load ratio and (3) assess the effects of early suppressive cART and telmisartan + cART intensification on MO inflammation.