MECHANISM OF HIV-1 ENTRY, REPLICATION, AND CYTOPATHOGENIC EFFECT IN NEURAL CELLS

  • Sharer, Leroy (PI)
  • Fisher, Paul (PI)
  • Potash, Mary Jane (PI)
  • Gelbard, Harris (PI)
  • Limoges, Jenae (PI)
  • Volsky, David (PI)
  • Volsky, David (PI)
  • Gendleman, Howard (PI)
  • Epstein, Leon (PI)
  • Blumberg, Benjamin (PI)
  • SHARER, LEROY (PI)
  • Volsky, David (PI)
  • Gendleman, Howard (PI)
  • Epstein, Leon (PI)
  • Blumberg, Benjamin (PI)
  • GENDELMAN (PI)
  • Gendleman, Howard (PI)
  • Epstein, Leon (PI)
  • Blumberg, Benjamin (PI)
  • Volsky, David (PI)
  • GENDELMAN (PI)
  • Fisher, Paul (PI)
  • Limoges, Jenae (PI)
  • SHARER, LEROY (PI)
  • GENDELMAN, HOWARD ELIOT (PI)
  • GENDELMAN, HOWARD (PI)

Project Details

Description

The general objective of this proposal is to study the biochemical and
molecular mechanisms governing the HIV-1 life-cycle in neural cells in
vitro, and the effects of HIV-1 on neural cell gene expression, as a
model for understanding HIV-1 neurotropism and its contribution to AIDS
encephalopathy. The proposed studies are based on our recent findings
which identified several different features of the HIV-1 life cycle in
neural cells (of glial, astroglial, or neuronal origin) compared to T
lymphocytes or macrophages. These include efficient fusion of HIV-1
envelope with CD4-negative neural cell membranes, limited viral
replication in spite of efficient fusion and entry, transient high-level
viral production in CD4-expressing neural cells, and efficient HIV-1 DNA
transcription that is partially independent of the Tat/TAR
transcriptional system. We hypothesize that these features constitute
the basis of HIV-1 neurotropism by allowing the selection of specific
viral variants, modulating cellular gene expression during transient
high-level HIV-1 DNA transcription, and creating a reservoir of inducible
virus in the neural tissue. These direct (albeit non-cytolytic)
interactions of macrophage-mediated neuronotoxicity and other effects of
HIV-1 infection, to be investigated in other component projects of this
Program Project.

The Specific Aims of Project 1 are: 1) To determine how HIV-1 entry
determines the outcome of HIV-1 infection in neural cells in vitro; 2)
To study the role of env, nef, and vif in HIV-1 neurotropism using
primary neurotropic HIV-1's and chimeric neural HIV-1 constructs; 3) To
investigate the transient high-level transcription of HIV-1 DNA in neural
cells in vitro, including the novel Tat/TAR-independent transcriptional
mechanism; 4) To identify cellular genes modulated during HIV-1 infection
in vitro and in vivo. The proposed studies will utilize HIV-1 strains
and molecular clones, recombinant vectors, cell lines, other reagents,
and experience in neural cell biology and molecular virology acquired
during the past several years of research on AIDS and HIV-1 in this
laboratory. In addition, close collaboration, exchange of information,
and reagents with other members in the Program Project will be essential
for Aims 1 and 2 (L. Epstein, Project 3; B. Blumberg, Core A; Aim 3 (H.
Gendelman, Project 2), and Aim 4 (L. Sharer, Project 4). We hope that
the proposed studies will yield significant new information regarding the
mechanism of HIV-1 infection and persistence in human neural cells,
adding to the comprehensive investigation of complementary HIV-1
neuropathogenic mechanisms in this Program Project.
StatusFinished
Effective start/end date1/1/018/31/10

ASJC

  • Medicine(all)
  • Neuroscience(all)
  • Clinical Neurology
  • Neurology
  • Infectious Diseases
  • Genetics
  • Molecular Biology
  • Virology
  • Pediatrics, Perinatology, and Child Health
  • Cell Biology
  • Pathology and Forensic Medicine
  • Immunology