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: 9138386
• 负责人: PAUL R CLAPHAM
• 金额: $ 25.13万
• 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/9138386
• 关键词: Adult; B-Lymphocytes; Basophils; Biology; Blood Cells; Blood Platelets; Bone Marrow; Brain; CXCR4 gene; 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; Staging; 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(申请人提供)：骨髓中的造血祖细胞(HPC)分化为髓系细胞和淋巴细胞系，分散到全身不同的组织中。多项研究表明，HPC在体外可以被HIV-1感染。我们的初步数据显示，嗜Mac R5变异体(适应于在巨噬细胞上使用低CD4)比非嗜Mac R5病毒更有效地感染脐带血HPC，通过细胞接触感染尤其有效。我们还表明，在体外感染的HPC可以存活，分化和增殖为成熟的髓系细胞。然后，成熟的细胞能够将病毒转移到敏感的目标细胞。我们的数据表明，感染单个HPC可能会产生大量HIV+成熟细胞。这样的成熟细胞将能够将艾滋病毒植入全身不同的组织。据报道，骨髓中的HIV序列与脑中的序列密切相关。这一结果与HIV+单核细胞(来自受感染的HPC)将HIV种子植入大脑是一致的，据报道，这种情况发生在晚期疾病中。其他有限的研究还没有证实这一点。然而，骨髓含有许多细胞类型，包括成熟的巨噬细胞和淋巴样细胞，因此采样HIV可能无法从HPC中检测到病毒。在这里，我们将评估纯化的HPC中的HIV序列，并将其与脑中的序列进行比较。在这个方案中，我们的主要目标是研究(1)HIV+患者骨髓中的HPC是否携带HIV，以及它们是否可以分化为髓系细胞或T细胞系细胞，然后将病毒转移到新细胞。以及(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存在从骨髓到脑的传播途径。我们提出了三个目标。目的1：确定HIV阴性成人骨髓HPC能否在体外被感染，以及它们是否具有分化为髓系细胞和T细胞系细胞的能力。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：确定来自HIV+骨髓的HPC是否受到感染，并能分化为受感染的髓系和T细胞系细胞。我们将测试HIV+骨髓HPC向T细胞和髓系细胞的分化，并确定成熟细胞是否携带传染性和可转移病毒。目的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序列是否与相同HIV+患者的大脑中存在的病毒准种密切相关。我们的假设是，HIV+HPC分化为成熟的髓系细胞和T细胞，这些细胞将HIV病毒传播到全身。如果得到支持，我们的结果将指出HPC在HIV发病机制和形成病毒库中的主要作用，这在以前还没有被认识到。这一新信息可能导致新的战略，以确定需要根除的艾滋病毒+HPC及其衍生物，如果要在体内消除艾滋病毒的话。