Regulation of Epstein Barr Virus Persistence

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The long-term objective of the proposed
research is to understand the mechanisms that enable Epstein-Barr virus (EBV)
to persist as a latent infection. The ability of EBV to persist within an
immunocompetent host underlies the most significant pathology associated with
this gamma-herpesvirus, namely the development of several distinct malignancies
and lymphoproliferacive disease. Unfortunately, relatively little is known at
the molecular level about the mechanisms that promote EBV persistence. Thus,
the insight gained from these studies should contribute significantly to our
understanding of EBV pathogenic potential and our ability to treat or prevent
EBV-associated disease. To reach our objective, we will address two basic
processes that contribute to EBV persistence and for which there are
significant gaps in our knowledge. These are the regulation of EBV gene
expression during restricted latency. i.e., the long-term virus carrier state,
and the disruption by EBV of the host's innate immunity to virus infection.

Three specific aims are proposed. Under Aim 1 we will address the mechanisms
that regulate expression during restricted latency of the EBV protein EBNA-1,
which is essential for maintenance of the EBV genome in tumor cells and for
long-term viral persistence in normal latently infected B cells. Under Aims 2
and 3, we will address the mechanisms by which EBV inhibits the endogenous type
I interferon (IFN) response and establishment of an antiviral state within
latently infected B cells. Specifically, in Aim 2 we will focus on
identification of the EBV protein(s) responsible for inhibition of the
induction of type I IFN expression in response to EBV infection during the
growth program of latency, which is crucial for establishment of the B-cell
pool that serves as the long-term reservoir of EBV. Under Aim 3, we will
address mechanisms by which EBV disrupts the host's innate antiviral response,
focusing on the effects of EBV infection and individual EBV genes on known
regulators of this response. Specifically, we will examine the biological
significance of an observed physical interaction between the EBV LMP-1 protein
and IRF-7, which mediates type 1 IFN-gene expression in response to viral
infection. Additionally, we will address the significance of the suppression of
several IFN-stimulated genes by the EBV EBER RNAs. In summary, the proposed
research will evaluate fundamental mechanisms that promote EBV persistence and
contribute to its success as a human pathogen, and thus should significantly
broaden our understanding of EBV biology and our potential to target
EBV-associated disease.
StatusFinished
Effective start/end date4/1/9212/31/06

Funding

  • National Cancer Institute: $266,110.00
  • National Cancer Institute: $254,174.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute: $267,000.00
  • National Cancer Institute
  • National Cancer Institute: $260,726.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute: $267,000.00
  • National Cancer Institute: $30,000.00

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