Project Details

Description

The progression of human immunodeficiency virus (HIV) infection from
asymptomatic infection to the development of AIDS is the result of a
complex series of interactions between the virus and the infected host.
Within an infected cell, both trans-acting viral gene products and cellular
transcriptional factors participate in the regulation of viral gene
expression and virus production, exerting their effects through cis-acting
regulatory sequences present in the HIV genome. The goals of this project
are to understand the roles that these regulatory sequences play in viral
replication and in the activation or suppression of the expression of
integrated HIV proviruses. Studies of the role of regulatory sequences in productive HIV infection
will be based on mutagenesis of regulatory elements in the long terminal
repeat (LTR) of an infectious molecular clone of HIV. These studies shall
focus on the role of the HIV NF-kB and Spl binding sites in HIV replication
in human T lymphocytes and monocytic cells; the function of other LTR sites
will also be studied and the effects of the substitution of heterologous
promoter/enhancer elements will be analyzed. Studies of the role of HIV regulatory sequences in chronically infected
cells will be undertaken using cell lines containing HIV proviruses, whose
expression can be induced. Techniques designed to study in vivo protein-
DNA interactions will be employed in the study of these cells and will
include DNAse hypersensitivity studies and in vivo footprinting assays.
Regions of DNA-protein interactions associated with the suppression or
activation of HIV production will be identified. Chronically infected cell
lines containing HIV proviruses with LTR deletions will also be constructed
to allow further study of the role of regulatory elements in expression of
integrated HIV proviruses. Additional studies will be aimed at identifying previously unrecognized
sites of DNA-protein interactions in the HIV genome and at identifying
previously cellular factors associated with the high level of HIV gene
expression seen in certain T cell lines. The long term goal of these studies is to develop a detailed understanding
of the cis-acting elements in the HIV genome that are responsible for the
activation or suppression of HIV gene expression and replication. Such an
understanding may aid in the development of therapeutic strategies for HIV
infection that would be aimed at blocking HIV gene expression, either by
interfering with known activators of HIV gene expression or by identifying
cellular inhibitors of viral expression.
StatusFinished
Effective start/end date12/1/9011/30/96

Funding

  • National Institutes of Health: $169,508.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $178,207.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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