FEATURED INVESTIGATOR
ELLIOTT DAN KIEFF, MD, PHD

Dr. Elliott Kieff ’s career in virology and molecular genetics began in the early 1970’s, just as the focus in medical research turned to discovery at the basic molecular and genetic level. He has played a seminal role in understanding the way in which Epstein-Barr virus (EBV) infects and immortalizes B lymphocytes, a process that contributes to a number of human malignancies, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. His viral oncology group at the Channing Laboratory focuses mainly on three oncogenic viruses: EBV; Kaposi’s sarcoma-associated herpesvirus, also known as human herpesvirus 8 (HHV8); and human papillomavirus (HPV), which has been implicated in cervical cancer.

 

Background

Dr. Kieff graduated from the undergraduate program of the University of Pennsylvania, with a major in Chemistry in 1963 and received a medical degree from the Johns Hopkins University in 1966. He trained as an intern and resident at the University of Chicago between 1966 and 1970. He then completed a postdoctoral program in microbiology at the University of Chicago and joined the faculty there as an assistant professor in medicine and virology in 1970. He was named Chief of Infectious Disease and Director of Interdepartmental Training in Infectious Disease in 1971. In 1975 he was promoted to associate professor in the Departments of Medicine and Molecular Genetics and Cell Biology, and to the Committees on Immunology and Virology. In 1985 he became a chaired professor (Louis Block) at Chicago. In the mid-1980’s, he was recruited by the Dean of Harvard Medical School, the Chair of the Department of Microbiology and Molecular Genetics at Harvard, and the Chair of the Department of Medicine at Brigham and Women’s Hospital to come to Boston to create an infectious disease program at the Channing Laboratory. He became a chaired professor at Harvard University (Ryan Albee Professor) in 1988. As Dr. Kieff relates, “The opportunity to reestablish a viral program here at the Channing Laboratory just across the street from the Brigham and Women’s Hospital and Harvard Medical School was an ideal situation for me.”

Research

Work in the Kieff laboratory is centered on understanding the molecular details of B cell transformation by EBV. Although EBV infection is benign and uneventful in the majority of people, there is a very strong link between EBV and certain human cancers, particularly those of B cell origin, such as post-transplant lymphoproliferative disorders, Burkitt lymphoma, and Hodgkin lymphoma. Primary infection of B cells by EBV is associated with the expression of a group of latency-associated proteins that collaborate to immortalize B cells. In the absence of an effective host T cell response, these proteins can cause the rapid outgrowth of B cell tumors. In most people, however, the T cell  response to infection is effective, and the virus persists in a small number of resting B cells for the life of the individual. This pool of B cells expresses only a small number of the genes encoded in the EBV genome. On occasion, however, the program of viral gene expression that drives B cell transformation is reactivated, and this can contribute to the development of B cell lymphomas. EBV is a large and complex virus that has adapted during millions of years of co-evolution with its primate hosts, such that most newly infected people develop no disease, or the transient disease known as infectious mononucleosis. Such individuals, however, carry the virus throughout life in a small number of B cells, and in the absence of a normal immune system, EBV reactivation in these cells can cause the rapid formation of B cell tumors (lymphomas). Dr. Kieff ’s lab has played a leading role in understanding many fundamental aspects of EBV infection, most notably how proteins made by viral genes stimulate the growth and survival of B cells, changes that eventually lead to tumor formation.

Laboratory

Dr. Kieff ’s laboratory is staffed by a group of 15 graduate students, postdoctoral trainees, and assistant professors.

 

funding

The majority of Dr. Kieff ’s funding comes the National Institutes of Health.

Collaborations

The researchers in Dr. Kieff ’s laboratory enjoy widespread collaborations locally, nationally, and internationally. As Dr. Kieff himself indicates, “The wonderful thing about science is that it is enormously crowded.”

Importance of Being at the Brigham

“The Brigham is certainly as rich an environment for understanding human biology as one could find anywhere on the surface of the earth,” relates Dr. Kieff. “We are not hindered in any respect by lack of colleagues with complementary expertise in human biology. We have experts in cell growth, cell survival, pathogenesis of infection, and immune responses to viruses. This is certainly the place to do that kind of work and I am very pleased to be here and to be making a contribution to enriching that environment in our own area of expertise, namely, virology, and to be able to take advantage of this environment to advance our own interests.”

Future

Specific projects that are currently ongoing in the lab are focused on understanding how the expression of viral genes is regulated, how viral proteins work together to alter gene expression, and the crucial EBV-mediated signals that dysregulate the growth and survival of EBV-infected B cells. “We hope that insights gained through these studies will reveal new pathogenic mechanisms and opportunities for therapeutic intervention in EBV-associated cancers,”  plains Dr. Kieff.

Selected References
  1. Kang MS, Lu H, Yasui, T, Sharpe A, Warren H, Cahir-McFarland E, Bronson R, Hung SC, Kieff E. Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVC mice. PNAS. 2005;102:820-825.
  2. Rainio EM, Ahlfors H, Carter KL, Ruuska M, Matikainen S, Kieff E, Koskinen PJ. Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity. Virology. 2005;333(2):201-206.
  3. Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E. Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16286-16291.
  4. Peng CW, Zhao B, Kieff E. Four EBNA2 domains are important for EBNALP coactivation. J Virol. 2004 Oct;78(20):11439-11442.
  5. Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM, Kieff E. Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J Virol. 2004 Apr;78(8):4108-4119
  6. Peng CW, Xue Y, Zhao B, Johannsen E, Kieff E, Harada S. Direct interactions between Epstein-Barr virus leader protein LP and the EBNA2 acidic domain underlie coordinate transcriptional regulation. Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):1033-1038.
  7. Luftig M, Yasui T, Soni V, Kang M-S, Jacobson N, Cahir-McFarland E, Seed B, Kieff E. Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kB activation. PNAS. 2004;101(1):141-146.
  8. Yasui T, Luftig M, Soni V, Kieff E. Latent infection membrane protein transmembrane FWLY is critical for intermolecular interaction, raft localization, and signaling. PNAS. 2004;101(1):278-283.
  9. Rosendorff A, Illanes D, David G, Lin J, Kieff E, Johannsen E. EBNA3C coactivation with EBNA2 requires a SUMO homology domain. J Virol. 2004;78:367-377.
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