MONONUCLEAR PHAGOCYTES, HIV, AND HEMATOPOIESIS

  • Bagby, Grover (PI)

Project: Research project

Project Details

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

ASJC

  • Medicine(all)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.