Mechanisms of Gene Regulation by EBV EBNA-1 Protein

Project: Research project

Description

hin B lymphocytes with little overt disease. However, a breakdown in immune surveillance, e.g., as a
consequence of AIDS, remains a significant risk factor for development of EBV-associated lymphoma,
underscoring the highly evolved equilibrium that exists between this potentially oncogenic herpesvirus and the
host immune system. This equilibrium is dependent on a selective down-regulation of EBV latency-associated
gene expression during establishment of persistent infection that ultimately restricts expression to viral genes
critical for maintenance of persistence, while precluding those with acute transforming properties and/or which
encode dominant epitopes recognized by the EBV-specific T-cell surveillance. A pivotal process in this
transition to restricted latency is a promoter switching event that enables exclusive expression of the essential
EBV genome-maintenance protein, EBNA-1, from the promoter Qp, which can be negatively regulated through
two EBNA-1 binding sites immediately downstream of its transcription start site. Our recent efforts to define the
mechanism of EBNA-1 repression revealed that it acts not by inhibition of transcription, as originally believed,
but by suppression of pre-mRNA processing. The principal significance of this autoregulation, furthermore, has
recently become apparent. Although EBNA-1 was earlier thought to be invisible to the host immune
surveillance as a consequence of its ability to inhibit in cis its degradation by the cell proteasome, thereby
preventing presentation of EBNA-1 peptide epitopes in association with HLA class I molecules, subsequent
studies indicated that cytotoxic T cells that recognize EBNA-1 not only exist, but that they are directed towards
peptides generated during actual synthesis of EBNA-1, not by the degradation of mature EBNA-1. Thus,
resistance to proteasomal degradation is secondary to the autoregulated expression of EBNA-1 as the primary
mechanism employed by EBV to restrict EBNA-1-specific T-cell killing. Further, recently described antiapoptotic
properties of EBNA-1 suggest that it may have tumorigenic potential. We hypothesize, therefore, that
the autoregulatory function of EBNA-1 is highly critical to EBV persistence and its associated pathogenic
potential: it ensures sufficient EBNA-1 for genome maintenance, while limiting EBNA-1 synthesis below a
threshold that, if exceeded, would subject latently infected B cells to elimination by EBNA-1-specific cytotoxic T
cells, and potentially oncogenic transformation. We propose three specific aims to help us reach our long-term
objective of defining the contribution of EBNA-1 autoregulation to EBV biology, immune evasion and
pathogenesis: 1) Define the mechanism of EBNA-1 autoregulation; 2) Elucidate the contributions of EBNA-1
autoregulation to the growth and restricted programs of latency; and 3) Define the respective roles of Qp and
Fp, an alternative adjacent EBNA-1 promoter, in EBV infection.
StatusFinished
Effective start/end date9/15/087/31/12

Funding

  • National Institutes of Health: $379,236.00
  • National Institutes of Health: $387,750.00
  • National Institutes of Health: $387,750.00

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Human Herpesvirus 4
Genes
Proteins
Homeostasis
EBV-encoded nuclear antigen 1
T-Lymphocytes
Maintenance
B-Lymphocytes
Epstein-Barr Virus Infections
Genome
Herpesviridae
RNA Precursors
Virus Latency
Epitopes
Immune System
Acquired Immunodeficiency Syndrome
Immune Evasion
Transcription Initiation Site
Proteasome Endopeptidase Complex
Cerebral Palsy