HIV INDUCED BONE MARROW DYSFUNCTION

    Project: Research project

    Description

    DESCRIPTION A large number of studies on hematopoietic progenitor cells either from
    patients with AIDS or from normal volunteers infected by HIV-1 ex-vivo,
    have clearly indicated that although a small population of CD34+ marrow
    cells can be infected by HIV-1, stem cells and progenitors are not
    readily infected in vitro and are almost never infected in vivo.
    However, experiments on myeloid failure in AIDS indicate that auxiliary
    cells of the marrow stroma, some of which can be infected by HIV-1, fail
    to support normal myeloid hematopoiesis, suggesting that auxiliary cells
    in the microenvironment, and not stem cells and progenitors, may be the
    primary cell population that accounts for HIV-1 induced hematopoietic
    dysfunction. Since bone marrow stromal cell progenitors, including
    microvascular endothelial cells, can express CD34, we tested the
    hypothesis that bone marrow microvascular endothelial cells from some
    patients with AIDS were the HIV-1 infected CD34+ population. Recently,
    using bone marrow cells from normal volunteers and from three consecutive
    AIDS patients, the applicants have discovered: (1) conditions that
    favor long-term cultures of bone marrow stromal cells enriched in
    microvascular endothelial cells (MVEC stroma), some of which express
    CD34; (2) that MVEC derived from all three patients with AIDS were
    productively infected by HIV-1 while no other stromal cell type was
    infected; and (3) hematopoietic growth factor gene expression induced
    by IL-I in HIV-1-infected MVEC stroma (compared to normal stroma
    enriched for MVEC) was quantitatively suppressed. The applicant propose
    a model of hematopoietic dysfunction in HIV-1 infection in which
    infected bone marrow MVEC cause, directly or indirectly, a decline in the
    supportive function of the marrow stroma such that hematopoiesis is
    inhibited. The application is designed to fully test this model by; (a)
    determining the incidence and stage-relatedness of HIV-1 infection of
    bone marrow MVEC in seropositive patients, (b) quantifying the capacity
    of HIV-1 infected MVEC- stroma to support growth of committed progenitor
    cells, (c) quantifying constitutive and induced expression of genes
    encoding hematopoietic growth factors, adhesion molecules, and mitotic
    inhibitors in HIV-1 infected stromal cells, and (d) confirming the
    cause-and-effect relationship between specific dysfunctions observed in
    our studies and HIV-1 per se, using genetic loss-of- function and gain-
    of-function analyses.
    StatusFinished
    Effective start/end date9/30/948/31/05

    Funding

    • National Institutes of Health
    • National Institutes of Health: $304,726.00
    • National Institutes of Health: $335,387.00
    • National Institutes of Health: $365,719.00
    • National Institutes of Health
    • National Institutes of Health: $356,506.00
    • National Institutes of Health: $330,094.00
    • National Institutes of Health
    • National Institutes of Health: $338,877.00
    • National Institutes of Health: $347,563.00

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    HIV-1
    Bone Marrow
    HIV
    Mesenchymal Stromal Cells
    Granulocyte-Macrophage Progenitor Cells
    Stromal Cells
    Acquired Immunodeficiency Syndrome
    Granulocyte Colony-Stimulating Factor
    Endothelial Cells
    Granulocyte-Macrophage Colony-Stimulating Factor
    Hematopoiesis
    Interleukin-6
    Lymphoma
    Cell Survival
    CD40 Ligand
    Germinal Center
    HIV Infections
    Bone Marrow Cells
    Stem Cells
    Interleukin-1

    ASJC

    • Medicine(all)