Defining brain pericytes as a novel and myeloid-derived HIV reservoir

摘要 HIV-1感染者患非艾滋病相关共病的风险更高，包括脑血管疾病 以及神经系统疾病。这些病理可能至少部分是由低水平的病毒复制驱动的 在感染艾滋病毒的大脑中持续存在，这可能导致免疫激活、慢性炎症和病毒 重新激活。对小胶质细胞、星形胶质细胞和脑周细胞的实验表明，这些细胞都有能力， 在不同程度上，窝藏艾滋病毒感染。我们开创了脑周细胞感染HIV-1病毒的先河， 并表明这些细胞具有使HIV-1感染的受体特征。最近的证据表明 周细胞个体发育研究表明，脑周细胞的一个重要亚群起源于髓系。 祖先。我们最近在患有HIV脑炎的人脑中证明了HIV-1感染的周细胞。 此外，我们新的和令人兴奋的初步数据表明，脑周细胞可能能够潜伏 感染和再激活，类似于其他髓系细胞。基于这些观察，我们假设 脑周细胞是HIV-1形成的关键细胞类型，尽管以前没有人认识到这一点 中南地区的水库。当前提案的首要目标是描述潜伏的艾滋病毒- 1脑周细胞感染是成功根除中枢神经系统储存库的必要步骤 艾滋病治愈。与这一目标一致，特定的目标将评估大脑中潜伏的艾滋病毒感染的形成。 体内和体外的周细胞。在一组有病毒感染史的人脑样本中 从国家神经艾滋病组织联盟(NNTC)获得的抑制，我们将确定是否 在HIV抑制的患者中，脑周细胞存在潜在的HIV-1感染(目标1)。此外，我们还将评估 潜伏感染HIV-1的人原代脑周细胞的转录特征(目标2)，并描绘 与艾滋病毒感染脑周细胞相关的功能结局(目标3)。 对周细胞在病毒脑HIV储存库发育中的作用的关注是一种创新和切割- EDGE概念性方法，与当前的RFA一致。关注周细胞作为一种新的髓系细胞 在艾滋病毒-1感染和脑储备库的背景下，人口也具有改变范式的潜力和 可能会在这一领域带来新的发现。计划中的实验将帮助我们更好地描述 在中枢神经系统的周细胞储存库，以便设计未来的储存库清除和艾滋病毒治愈的治疗方法。

ABSTRACT HIV-1-infected individuals are at a higher risk for non-AIDS related co-morbidities, including cerebrovascular and neurological diseases. These pathologies may be driven, at least in part, by low levels of viral replication that persist in HIV-infected brains, which can lead to immune activation, chronic inflammation, and viral reactivation. Experiments on microglia, astrocytes, and brain pericytes indicate that these cells are all capable, to different degrees, to harbor HIV infection. We have pioneered research on HIV-1 infection in brain pericytes, and indicated that these cells possess the receptor profile enabling HIV-1 infection. Recent evidence on pericyte ontogeny identified that a substantial subpopulation of brain pericytes originates from myeloid progenitors. We recently demonstrated HIV-1-infected pericytes in human brains with HIV encephalitis. Furthermore, our new and exciting preliminary data suggest that brain pericytes may be capable of latent infection and reactivation, similar to other myeloid cells. Based on these observations, we hypothesize that brain pericytes are a key, albeit previously unrecognized, cell type for the formation of HIV-1 reservoirs in the CNS. The overarching goal of the current proposal is to characterize the latent HIV- 1 infection in brain pericytes as the necessary step for successful eradication of CNS reservoirs and HIV cure. Consistent with this goal, Specific Aims will evaluate the formation of latent HIV infection in brain pericytes both in vivo and in vitro. In a cohort of human brain samples with a history of achieved viral suppression obtained from the National NeuroAIDS Tissue Consortium (NNTC), we will determine whether brain pericytes harbor latent HIV-1 infections in HIV-suppressed patients (Aim 1). In addition, we will evaluate transcriptional signatures of latently HIV-1-infected human primary brain pericytes (Aim 2), and delineate functional outcomes associated with HIV infection of brain pericytes (Aim 3). The focus on the role of pericytes in the development of viral brain HIV reservoirs is an innovative and cutting- edge conceptual approach, consistent with the current RFA. Focusing on pericytes as a novel myeloid cell population in the context of HIV-1 infection and brain reservoirs has also a paradigm-changing potential and is likely to lead to new discoveries in the field. The planned experiments will help us to better characterize the pericyte reservoirs in the CNS in order to design future therapies for reservoir clearance and HIV cure.