HIV INDUCED BONE MARROW DYSFUNCTION

  • Bagby, Grover (PI)

Project: Research project

Project Details

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

ASJC

  • Medicine(all)

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