GLYCOSAMINOGLYCAN RECEPTORS FOR HSV-1 AND HSV-2

Project: Research project

Project Details

Description

Herpes viruses are responsible for significant disease both in
immunocompetent and immunocompromised hosts. Despite the clinical
importance of these viruses, little can be done to prevent herpes virus
infections or reactivation of latent disease. To develop better strategies
for prevention and treatment, a thorough understanding of the mechanism by
which these viruses cause disease and by which certain cells and tissues
are preferred targets for infection is critical. Recent studies, using
fibroblast and epithelial cell lines, have shown that heparan sulfate (HS)
glycosaminoglycans (GAGs) of cell surface proteoglycans serve as receptors
for the human herpesviruses, herpes simplex virus type 1 (HSV-1) and
herpes simplex virus type 2 (HSV-2). For HSV-1, it has been shown that the
viral envelope glycoproteins, gC and gB, can independently mediate this
attachment, although gC plays a key role. The viral glycoprotein(s)
responsible for the binding of HSV-2 to the cell surface are not yet
known. In addition, although HSV-1 and HSV-2 both bind to HS, it is not
yet known whether the two serotypes of HSV bind to the same or different
structural features of HS. Differences in receptors for the two serotypes
may help explain differences in cell and tissue tropism, as well as
differences in pathogenicity.

The studies proposed in this grant application will define the specific
structural features of the viral glycoproteins and cell surface GAGs
important in the entry of HSV-1 and HSV-2 into cells. The aims of these
studies are first to determine which glycoproteins mediate the binding of
HSV-2 to cells by generating mutant viruses deficient in the potential
heparin-binding glycoproteins. Second, the structural features of HS
important for viral attachment of HSV-1 and HSV-2 will be defined using a
series of chemically and enzymatically modified heparins. Compounds
identified that differentiate binding of individual glycoproteins of both
HSV-1 and HSV-2 to cell surface HS will be exploited in studies designed
to map the heparin-binding domains of the individual glycoproteins. These
studies will use a combination of recombinant viruses and site-directed
mutagenesis. By biochemically and molecularly characterizing cell surface
receptors and viral glycoproteins that mediate attachment of HSV- 1 and
HSV-2 to cells, these studies should enhance our understanding of viral
pathogenesis and tropism and may lead to the development of new approaches
to antiviral therapy, vaccine development, and gene therapy.
StatusFinished
Effective start/end date9/1/958/31/96

Funding

  • National Institute of Allergy and Infectious Diseases

ASJC

  • Drug Discovery
  • Molecular Medicine
  • Structural Biology
  • Biochemistry
  • Virology

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