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（由适用提供）：骨髓中的造血祖细胞（HPC）分化为髓样细胞和淋巴样细胞谱系，可分散到整个体内的不同组织中。几项研究表明，HPC可以在体外被HIV-1感染。我们的初步数据表明，与非非MAC-热带R5病毒相比，Mac-Tropic R5变体（适用于巨噬细胞在巨噬细胞上使用低CD4）更有效地感染脐带血HPC，并且通过细胞接触的感染特别有效。我们还表明，在体外感染的HPC可以分化并繁殖成成熟的髓样细胞。然后，成熟的细胞能够将病毒转移到易感靶细胞上。我们的数据表明，单个HPC的感染可能会产生大量的HIV+成熟细胞。这种成熟的细胞将能够将HIV染成整个体内的不同组织。据报道，骨髓中的HIV序列与大脑中的HIV序列密切相关。该结果与HIV+单核细胞（源自感染的HPC衍生成）将HIV接种到大脑中，这是据报道在晚期疾病中发生的。其他有限的研究尚未证实这一点。但是，骨髓包含许多细胞类型，包括成熟的巨噬细胞和淋巴样细胞，因此HIV的采样可能无法检测到HPC的病毒。在这里，我们将评估纯化的HPC中的HIV序列，并将其与大脑中的HIV序列进行比较。在此提案中，我们的主要目标是研究（1）来自HIV+受试者骨髓的HPC是否带有HIV，以及它们是否可以区分髓样或T细胞谱系细胞，然后将病毒转移到新细胞中。 （2）HPC中存在的HIV序列是否与脑组织中的HIV序列有关，以支持骨髓到HIV的脑部扩散途径的存在。我们提出三个目标。目标1：确定HIV阴性成年骨髓HPC是否可以在体外感染HPC，以及它们是否保留分化为髓样和T细胞谱系细胞的能力。我们将测试我们的数据是否显示出脐带血HPC的HIV感染和分化适用于成年骨髓HPCS AIM 2：确定来自HIV+骨髓的HPC是否感染了HPC，并可以分化为感染的髓样和T细胞谱系细胞。我们将测试HIV+骨髓HPC的分化为T细胞和髓样谱系细胞，并确定成熟细胞是否具有感染性和转移的病毒。 AIM 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序列是否与同一患有HIV相关神经认知疾病（HAND）的同一HIV+患者的大脑中存在的病毒式准蛋白质密切相关。我们的假设是HIV+ HPC分化为分散HIV的成熟髓样和T细胞。如果得到支持，我们的结果将指出HPC在HIV发病机理和形成病毒储备中的主要作用，这些病毒储量以前尚未得到理解。这些新信息可能会导致新的策略，以识别如果要在体内消除HIV，则需要放射放射艾滋病毒+ HPC和衍生物。