HIV-1 infection of hematopoietic progenitor cells, their differentiation and seeding of virus into brain tissue

HIV-1 造血祖细胞的感染、其分化以及病毒植入脑组织

• 批准号: 9232227
• 负责人: PAUL R CLAPHAM
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232227
• 关键词: Adult; B-Lymphocytes; Basophils; Biology; Blood Cells; Blood Platelets; Bone Marrow; Brain; CXCR4 gene; Cell Differentiation process; Cell Lineage; Cells; Data; Dendritic Cells; Disease; Erythrocytes; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Hematopoietic stem cells; Immune; In Vitro; Infection; Lead; Lymphoid Cell; Megakaryocytes; Myelogenous; Myeloid Cells; Natural Killer Cells; Organ; Pathogenesis; Patients; Pharmacotherapy; Play; Reporting; Role; Route; Sampling; Seeds; Site; Stem cells; T-Lymphocyte; Testing; Tissues; Umbilical Cord Blood; Umbilical cord structure; Variant; Viral; Viral reservoir; Virus; Virus Diseases; brain tissue; cell type; eosinophil; in vivo; killings; macrophage; monocyte; neutrophil; progenitor; public health relevance; trafficking

 DESCRIPTION (provided by applicant): Hematopoietic progenitor cells (HPCs) in bone marrow differentiate into both myeloid, and lymphoid cell lineages that disperse into different tissues throughout the body. Several studies indicate that HPCs can be infected by HIV-1 in vitro. Our preliminary data shows that mac-tropic R5 variants (adapted to use low CD4 on macrophages) infect umbilical cord blood HPCs more efficiently than non-mac-tropic R5 viruses and that infection via cell contact is particularly efficient. We also show that HPCs infected in vitro survive to differentiate and multiply into mature myeloid cells. Mature cells were then able to transfer virus to susceptible target cells. Our data indicates that infection of a single HPC would have the potential to produce large numbers of HIV+ mature cells. Such mature cells would be able to seed HIV into different tissues throughout the body. HIV sequences in bone marrow were reported to be closely related to those in brain. This result is consistent with HIV+ monocytes (derived from infected HPCs) seeding HIV into the brain, as reported to occur in late disease. Other limited studies have not confirmed this. However, bone marrow contains many cell types including mature macrophages and lymphoid cells, so that sampling of HIV may not detect virus from HPCs. Here, we will evaluate HIV sequences in purified HPCs and compare them with those in brain. In this proposal, our main goals are to investigate (1) whether HPCs from bone marrow of HIV+ subjects carry HIV and whether they can differentiate into myeloid or T-cell lineage cells that then transfer virus to new cells. And (2) whether HIV sequences present in HPCs are related to those in brain tissue, to support the presence of a bone marrow to brain dispersal route for HIV. We present three aims. Aim 1: Determine whether HIV-negative adult bone marrow HPCs can be infected in vitro and whether they retain the capacity to differentiate into myeloid and T-cell lineage cells. We will test if our data showing HIV infection and differentiation of umbilical cord blood HPCs applies to adult bone marrow HPCs Aim 2: Determine whether HPCs derived from HIV+ bone marrow are infected and can differentiate into infected myeloid and T-cell lineage cells. We will test differentiation of HIV+ bone marrow HPCs into both T- cell and myeloid lineage cells and establish whether mature cells carry infectious and transferable virus. Aim 3: Establish whether HIV sequences in HPCs are closely related to those in brain tissue. We will examine whether HIV sequences present in HIV+ bone marrow HPCs are closely related to viral quasispecies present in the brain of the same HIV+ patients with HIV-associated neurocognitive disorder (HAND). Our hypothesis is that HIV+ HPCs differentiate into mature myeloid and T-cells that disperse HIV through the body. If supported, our results will point to a major role for HPCs in HIV pathogenesis and formation viral reservoirs that has previously not been appreciated. This new information may lead to new strategies to identify HIV+ HPCs and derivatives that need to be eradicated if HIV is to be eliminated in vivo.

 描述（由申请人提供）：骨髓中的造血祖细胞（HPC）分化为骨髓细胞和淋巴细胞谱系，并分散到全身不同的组织中。多项研究表明 HPC 可以在体外被 HIV-1 感染。我们的初步数据表明，mac-tropic R5 变体（适合在巨噬细胞上使用低 CD4）比非 mac-tropic R5 病毒更有效地感染脐带血 HPC，并且通过细胞接触进行的感染特别有效。我们还表明，体外感染的 HPC 能够存活并分化并增殖成成熟的骨髓细胞。然后成熟细胞能够将病毒转移到易感靶细胞。我们的数据表明，单个 HPC 的感染有可能产生大量 HIV+ 成熟细胞。这些成熟的细胞能够将艾滋病毒传播到全身的不同组织中。 据报道，骨髓中的艾滋病毒序列与大脑中的序列密切相关。这一结果与 HIV+ 单核细胞（源自受感染的 HPC）将 HIV 植入大脑的情况一致，据报道，这种情况发生在疾病晚期。其他有限的研究尚未证实这一点。然而，骨髓含有许多细胞类型，包括成熟的巨噬细胞和淋巴细胞，因此 HIV 采样可能无法从 HPC 中检测到病毒。在这里，我们将评估纯化 HPC 中的 HIV 序列，并将其与大脑中的序列进行比较。 在本提案中，我们的主要目标是研究 (1) 来自 HIV+ 受试者骨髓的 HPC 是否携带 HIV，以及它们是否可以分化为骨髓或 T 细胞谱系细胞，然后将病毒转移到新细胞。 (2) HPC 中存在的 HIV 序列是否与脑组织中的序列相关，以支持 HIV 存在从骨髓到大脑的传播途径。我们提出三个目标。目标 1：确定 HIV 阴性成人骨髓 HPC 是否可以在体外被感染，以及它们是否保留分化为骨髓和 T 细胞谱系细胞的能力。我们将测试显示 HIV 感染和脐带血 HPC 分化的数据是否适用于成人骨髓 HPC 目标 2：确定源自 HIV+ 骨髓的 HPC 是否被感染并可以分化为受感染的骨髓和 T 细胞谱系细胞。我们将测试 HIV+ 骨髓 HPC 分化为 T 细胞和骨髓谱系细胞，并确定成熟细胞是否携带传染性和可转移病毒。目标 3：确定 HPC 中的 HIV 序列是否与脑组织中的 HIV 序列密切相关。我们将检查 HIV+ 骨髓 HPC 中存在的 HIV 序列是否与患有 HIV 相关神经认知障碍 (HAND) 的同一 HIV+ 患者大脑中存在的病毒准种密切相关。 我们的假设是，HIV+ HPC 分化为成熟的骨髓细胞和 T 细胞，将 HIV 传播到全身。如果得到支持，我们的结果将表明 HPC 在 HIV 发病机制和病毒储存库形成中发挥着重要作用，而这一作用此前尚未得到重视。这一新信息可能会带来新的策略来识别 HIV+ HPCs 和衍生物，如果要在体内消除 HIV，则需要根除这些 HIV+ HPCs 和衍生物。