MONONUCLEAR PHAGOCYTES, HIV, AND HEMATOPOIESIS

    Project: Research project

    Description

    Mononuclear phagocytes play a central role in regulating hematopoiesis
    and phagocyte function. First, they produce hematopoietic growth factors
    and, secondly, they express interleukin-1 and tumor necrosis factor-alpha
    gene products which function to induce other cells in the hematopoietic
    microenvironment to produce multilineage hematopoietic growth factors.
    Virtually all of the induced hematopoietic growth factors are known to
    have stimulatory effects not only on the proliferative activity of
    hematopoietic progenitor cells but on the functional activity of
    terminally differentiated phagocytes. A convincing body of evidence
    demonstrates that mononuclear phagocytes are important target of HIV-1
    infection, and that proviral integration can alter the regulated
    production of IL-1. Because regulated expression of CSF an interleukin
    genes is essential for normal hematopoietic and phagocytic function, and
    because patients with HIV infection commonly exhibit disorders of both
    processes, we hypothesize that hematopoietic and phagocyte dysfunction in
    such patients are the direct result of infection of mononuclear
    phagocytes by HIV. We will test this hypothesis in the first aim of our
    studies. Specifically, we will determine the effects of latent HIV
    infection on both hematopoietic and phagocytic function of mononuclear
    phagocytes and will determine the molecular mechanisms by which these
    effects occur. Certain physiologic signals, including GM-CSF, can induce the expression
    of HIV in latently infected cells. We hypothesize that multiple
    hematopoietic growth factors and interleukins induce the expression of
    provirus in latently infected mononuclear phagocytes and that this effect
    is mediated, at least in part, by the induction of specific viral
    regulatory proteins or cellular transcription factors known to affect HIV
    expression. We will test these hypotheses in the second aim of this
    proposal. Specifically, we will determine the effects of recombinant
    human hematopoietic growth factors and interleukins on proviral
    expression by HIV infected mononuclear phagocytes and analyze the
    molecular mechanisms by which either stimulatory or inhibitory effects
    occur. The results of our studies should provide a strong rationale for
    the development of therapeutic strategies which might circumvent
    progressive hematopoietic dysfunction (Aim 1) without the risk of
    accelerating HIV infection(AIM 2).
    StatusFinished
    Effective start/end date2/1/891/31/95

    Funding

    • National Institutes of Health
    • National Institutes of Health: $232,139.00
    • National Institutes of Health
    • National Institutes of Health: $215,524.00
    • National Institutes of Health

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    Hematopoiesis
    Phagocytes
    HIV
    Intercellular Signaling Peptides and Proteins
    HIV Infections
    Interleukins
    Interleukin-1
    Granulocyte-Macrophage Colony-Stimulating Factor
    Transcription Factors
    Stem Cells
    Tumor Necrosis Factor-alpha
    Growth
    Proteins

    ASJC

    • Medicine(all)