Role of Myeloid Cells in HIV latency in the Periphery and the CNS

骨髓细胞在外周和中枢神经系统 HIV 潜伏期中的作用

• 批准号: 8846414
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 59.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846414
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; B-Lymphocytes; Biology; Bone Marrow; Brain; Cells; Complement; Dendritic Cells; Development; Disease; Disease Progression; Epidemic; Frequencies; Functional disorder; Grant; HIV; HIV Infections; HIV-1; Human; Infection; Intervention; Investigation; Laboratories; Liver; Maintenance; Modeling; Mus; Myelogenous; Myeloid Cells; Neuraxis; Pathogenesis; Predisposition; Process; Production; Research; Residual state; Role; T-Lymphocyte; Thymus Gland; Time; Tissues; Viral; Virus; antiretroviral therapy; in vivo; innovation; killings; macrophage; monocyte; mouse model; novel; novel strategies; public health relevance; transmission process

 DESCRIPTION: From the earliest days of the AIDS epidemic, monocytes and macrophages have been shown to be key players in the establishment and maintenance of HIV infection (1). The importance of monocyte/macrophages in all aspects of the infectious process has been extensively documented (2). Most notably, their role in the establishment and maintenance of infection in the central nervous system (CNS) has been fully appreciated (3). Over the last several years, our laboratory has made significant progress towards the development and implementation of humanized mice for HIV research. In particular, we have established critical parameters for the use of bone marrow/liver/thymus (BLT) humanized mice and T cell only mice (ToM) for the analysis of latency and eradication. Specifically, we have established effective antiretroviral therapy (ART) that results in viral suppression, established the development of latently HIV infected T cells, quantitated the frequency of latently infected cells systemically an per tissue, and demonstrated that latency can be disrupted ex-vivo after induction resulting in virus production. Finally, we implemented novel approaches to kill HIV infected T cells that compose the residual active reservoir that persist in vivo despite ART. Through a parallel line of investigation, we have recently implemented a novel animal model that differs from all other existing humanized mouse models used to study HIV in one important fact: it does not contain any human T cells. Instead, in addition to human B cells, it contains a complete complement of myeloid cells including monocytes, macrophages and dendritic cells all of which are important targets for HIV infection, pathogenesis, transmission, persistence and disease progression. The availability of a model in which only the human myeloid-cells present in all tissues including the brain are targets of HIV infection (designated MoM, for myeloid only mice) permits, for the first time, detailed in vivo study of the role of myeloid cells in HIV infection, dissemination, pathogenesis, latency and persistence. As part of this grant we propose to carry out the following Specific Aims: 1) To establish the susceptibility of humanized MoM to HIV-1 infection by macrophage- and T cell-tropic viruses. Hypothesis: Macrophages are sufficient to sustain HIV replication in vivo in the absence of human T cells. MoM can serve as a highly innovative model in which to study in detail the biology and pathogenesis of HIV infection in myeloid cells in vivo. 2) To determine the effect of ART on HIV-1 replication in humanized MoM. A better understanding of the role of myeloid cells in HIV persistence requires the establishment of robust pharmacological interventions capable of efficiently suppressing HIV replication in this compartment. Hypothesis: Highly active triple combination antiretroviral therapy is effective at suppressing HIV replication in macrophages in vivo. 3) To characterize the role of macrophages on the establishment and maintenance of the latent HIV reservoir in the periphery and in the brain of humanized MoM. Hypothesis: Macrophages represent a reservoir of HIV that contributes to HIV persistence in vivo.

 产品说明：从艾滋病流行的最早期开始，单核细胞和巨噬细胞已被证明是建立和维持HIV感染的关键参与者（1）。单核细胞/巨噬细胞在感染过程的各个方面的重要性已被广泛记录（2）。最值得注意的是，它们在中枢神经系统（CNS）感染的建立和维持中的作用已得到充分认识（3）。在过去的几年里，我们的实验室在开发和实施用于HIV研究的人源化小鼠方面取得了重大进展。特别是，我们已经建立了使用骨髓/肝脏/胸腺（BLT）人源化小鼠和仅T细胞小鼠（ToM）进行潜伏期和根除分析的关键参数。具体而言，我们已经建立了有效的抗逆转录病毒疗法（ART），其导致病毒抑制，建立了潜伏性HIV感染的T细胞的发育，定量了全身和每个组织的潜伏性感染细胞的频率，并证明了在诱导后潜伏期可以被离体破坏，导致病毒产生。最后，我们实施了新的方法来杀死HIV感染的T细胞，这些T细胞构成了尽管ART仍在体内存在的残留活性库。通过平行的调查，我们最近实施了一种新的动物模型，该模型与用于研究HIV的所有其他现有人源化小鼠模型不同，其中一个重要事实是：它不包含任何人类T细胞。相反，除了人B细胞外，它还含有完整的髓样细胞补体，包括单核细胞、巨噬细胞和树突细胞，所有这些细胞都是HIV感染、发病、传播、持续和疾病进展的重要靶标。其中仅存在于包括脑在内的所有组织中的人骨髓细胞是HIV感染的靶点的模型（指定为MoM，用于仅骨髓的小鼠）的可用性允许首次详细地在体内研究骨髓细胞在HIV感染、传播、发病机制、潜伏期和持续性中的作用。作为该资助的一部分，我们计划开展以下具体目标：1）确定人源化MoM对嗜巨噬细胞和嗜T细胞病毒的HIV-1感染的易感性。假设：在没有人T细胞的情况下，巨噬细胞足以维持HIV在体内的复制。MoM可以作为一种高度创新的模型，在其中详细研究体内骨髓细胞中HIV感染的生物学和发病机制。2)确定ART对人源化MoM中HIV-1复制的影响。要更好地了解骨髓细胞在HIV持续存在中的作用，需要建立能够有效抑制HIV在该区域复制的强大的药理学干预措施。假设：高活性三联抗逆转录病毒疗法在体内抑制巨噬细胞中的HIV复制是有效的。3)表征巨噬细胞在人源化MoM外周和脑中潜伏HIV储库的建立和维持中的作用。假设：巨噬细胞是艾滋病毒的储存库，导致艾滋病毒在体内持续存在。