SIV CNS DISEASE--A MODEL OF AIDS ENCEPHALOPATHY

  • Hildreth, James (PI)
  • Zink, Christine (PI)
  • Adams, Robert (PI)
  • Clements, Janice (PI)

Project: Research project

Project Details

Description

The majority of HIV-infected adults and children suffer neurological
impairment. Studies of HIV-associated dementia complex have repeatedly
demonstrated that HIV-1 replicates in cells of macrophage lineage
(microglia), and virus cultured from the brains usually macrophage-
tropic. Studies of the pathogenesis of HIV in the CNS have been limited
by the difficulty of studying the progression of disease. The timing and
mechanisms of viral entry into the brain and the viral determinants of
neurotropism are incompletely understood. the SIV/macaque model provides
an excellent system to determine the early events in CNS infection and
to reconstruct the events leading to terminal disease. Genetically
defined clones of SIV make it possible to investigate the viral genes
that contribute to cell tropism and gene expression in the CNS. Our
hypothesis is that a tropism for macrophages is a prerequisite for both
HIV and SIV to infect cells in the CNS. However, further selection for
virus replication in CNS cells is necessary for infection and progression
of disease. These neurotropic viruses enter the brain through the blood-
brain barrier by mechanism(s) which may involve expression of cell
adhesion molecules on virus or virus-infected cells, and replicate in
macrophages in brain. Pathological changes in the CNS may be a function
of the level of viral replication in target cells. This
interdisciplinary program on the SIV/macaque model will allow us to
investigate this hypothesis both in vivo and in vitro. Project 1 will
investigate the timing of viral entry into the brain, the mechanisms by
which the virus crosses the blood-brain-barrier and the events in cells
of the CNS that lead to disease. Project 2 will examine how cellular
adhesion molecules affect viral entry, cell tropism and the host response
to the virus. Project 3 will examine the genetic basis of macrophage-
tropism and neurotropism. The molecular events involved in SIV infection
in the brain and in primary brain cells (microglia and endothelial
cells). This program approaches the development of lentivirus-induced
CNS disease from three disciplines, pathobiology, cell biology and
molecular biology and contribute to the overall understanding of the
viral and cellular mechanisms that contribute to CNS encephalopathy in
SIV and HIV. These studies will provide a basic understanding of how HIV
enters the brain and causes neural dysfunction and will provide
information critical to the development of rational interventional and
therapeutic approaches to HIV-induced disease.
StatusFinished
Effective start/end date9/1/933/31/98

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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