Monocytes and HIV CNS Reservoirs in Super Acute HIV Infection

描述(由申请人提供)：这项建议旨在定义急性艾滋病毒感染(AHI)期间引起的单核/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)的时机在防止长期HIV诱导的单核/巨噬细胞(MO)表型和功能变化和MO的HIV感染方面的作用。在最初暴露于艾滋病毒建立中枢神经系统(CNS)感染库的背景下，拟议的目标将描述持久性艾滋病毒库的特征，这可能有助于我们理解制定治疗艾滋病毒-1感染的创新战略。MO特征的改变和MO HIV负担的程度与神经认知障碍(NCI)的发展密切相关。由于受到干扰的MO种群的脑损伤可能在接触HIV后很早就发生，因此了解HIV感染最早阶段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，我们的实验室最近在慢性HIV中发现了一种扰动的表型和功能MO谱，这有助于NCI的发生，并证明MO具有与NCI相关的高HIV负担。与NIH资助的RV254/Search 010队列的研究人员合作，泰国曼谷的100多例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学测量，包括脑脊液(CSF)炎症评估和脑的磁共振波谱(MRS)，确定AHI期间单核细胞的最早变化。我们已经确定了从HIV暴露开始的平均2周的感染时间，并确定了全身和脑脊液细胞反应和HIV病毒负担的模式。我们建议在AHI中定义MO特征和病毒负荷上升到类似于慢性感染的高水平的最早时间点，并将其与(1)早期神经侵袭相关，其特征是MRS检测到的CNS炎症和脑实质炎症的可测量循环标志物，(2)通过脑脊液/血浆HIV病毒载量比率评估基线病毒渗透，以及(3)评估早期抑制CART和替米沙坦+CART强化对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.