Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1

PLoS Pathog. 2010 Dec 23;6(12):e1001236. doi: 10.1371/journal.ppat.1001236.


Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Burkitt Lymphoma / etiology
  • Burkitt Lymphoma / virology*
  • Drug Resistance
  • Herpesvirus 4, Human / pathogenicity*
  • Host-Pathogen Interactions
  • Mice
  • Protein Binding
  • Viral Proteins / metabolism
  • Viral Proteins / physiology*


  • Apoptosis Regulatory Proteins
  • BHRF1 protein, Human herpesvirus 4
  • Viral Proteins