Monocytes and HIV CNS Reservoirs in Super Acute HIV Infection

描述（由申请方提供）：本提案旨在定义急性HIV感染（AHI）期间诱导的单核细胞/巨噬细胞（MO）表型和功能的早期变化，并确定早期启动联合抗逆转录病毒治疗（cART）的时机在预防HIV诱导的MO特征长期改变和MO HIV感染中的作用。在最初暴露于HIV（建立了中枢神经系统（CNS）感染库）的背景下，拟议的目标将描述持续的HIV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 HIV负荷的程度与神经认知障碍（NCI）的发展密切相关。由于脑损伤涉及扰动MO人群可能发生在暴露于HIV后的早期，因此了解MO扰动在HIV感染的最早阶段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中受干扰的表型和功能MO概况，这有助于NCI，并证明MO具有与NCI相关的高HIV负荷。在与NIH资助的RV 254/RV 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），确定AHI期间单核细胞的最早变化。我们已经确定了感染的时间，平均从HIV暴露开始后2周，并确定了全身和CSF细胞反应的模式和HIV病毒负荷。我们建议定义AHI中最早的时间点，其中MO特征和病毒负荷上升到类似慢性感染的高水平，并将其与（1）早期神经侵袭相关，其特征在于可测量的CNS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病毒载量比评估的基线病毒渗透率和（3）评估早期抑制性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.