FEATURED INVESTIGATOR
FRED WANG, MD

Dr. Fred Wang’s research concerns the pathogenesis of Epstein-Barr Virus (EBV) infection: how it successfully infects humans, how it persists in humans, and how and why it is associated with certain kinds of cancer. Epstein-Barr is a very common virus that infects nearly all humans by adulthood. Once infected, we are host to the virus for life. Most people in developing countries are infected very early in life. In the developed world, however, infection often does not occur until adolescence, and the immune system frequently responds very vigorously to the infection, giving rise to the syndrome known as infectious mononucleosis. In normal people the immune system eventually controls the infection, but is unable to completely eliminate the virus, which persists for life in a number of latently infected B cells. In  imunocompromised individuals, this balance is disrupted and EBV-infected B cells proliferate uncontrollably, causing lymphomas. In other individuals, persistent EBV infection can be associated with the development of nasopharyngeal carcinoma, Hodgkin Lymphoma, Burkitt Lymphoma, and a number of other cancers.

Background

Dr. Wang was born and raised in the Midwest. In 1980, he graduated from the Honors Program in Medical Education at Northwestern University, a six-year program that grants both undergraduate and medical degrees. He trained as an intern and resident at the University of California, San Francisco, finishing his clinical training in 1983. Between 1983 and 1985 he was an immunology research fellow at the National Cancer Institute, Metabolism Branch, and thereafter moved back to Chicago for an infectious disease fellowship and research training in molecular virology with Dr. Elliott Kieff at the University of Chicago. In 1987, Drs. Wang and Kieff came to the Channing Laboratory, an intramural research facility of the Harvard Medical School and the Brigham and Women’s Hospital. The Channing Laboratory, an arm of the Brigham’s Department of Medicine, has three main focuses: epidemiology, bacteriology, and virology. “Our laboratory,” Dr. Wang relates, “is part of the virology group which focuses on EBV, Kaposi’s sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV), which is associated with cervical cancer.” Dr. Wang is also the Medical Director of the Clinical Virology Laboratory at the Brigham & Women’s Hospital, a position he has held now for many years.

Research

Dr. Wang’s laboratory developed the first animal model for EBV infection, which reproduces the natural route of transmission, acute and persistent infection, and associated oncogenesis that is seen in humans. His research is centered on understanding how the virus successfully infects and persists in the host. Much research has focused on a limited number of viral genes that are important for viral replication and virus-induced B cell growth. The development of an accurate animal model for EBV infection now provides a means through additional research to determine how viral genes help the virus to successfully infect the host. Once infection occurs, EBV must evade the immune response, persist, and periodically replicate to generate infectious virus that perpetuates the virus life cycle by infecting new, naive hosts. EBV encodes approximately 90 genes, but the function of most of these genes is unknown. Understanding how these viral genes function to alter the host cell and facilitate virus infection and survival in the competent host will provide important insights into new strategies to disrupt the virus life cycle and prevent diseases associated with EBV infection.

 

EBV-related nasopharyngeal cancer, a further focus of Dr. Wang’s research, is very prevalent in Southeast China and certain Eskimo populations, where it is one of the most common cancers. The basis for its prevalence in particular human populations is unclear, but it may stem from dietary factors or differences in genetic predisposition. As Dr Wang states, “It is not obvious at this time whether these individuals develop a virus-infected cancer in the face of an intact immune response to the virus, or if there is a specific immune defect that is responsible for tumorigenesis in these individuals. These are the questions we need to explore.”

 

Dr. Wang’s translational efforts are presently focused on augmenting the immune response to treat EBV-related nasopharyngeal cancers. Specifically, Dr. Wang and his colleagues are studying the use of ‘adoptive immunotherapy’ with EBV-specific T-cells. T-cells are obtained from patients and stimulated in culture with the virus-infected B cells to expand the number of EBV-specific T-cells, then infused back into the patient, where the amplified T-cells attack the EBV-infected tumor cells.

Laboratory

The laboratory consists of four postdoctoral fellows, one graduate student, and two technicians. As Dr. Wang explains, “My laboratory is small because I prefer to work with a tight knit group.”

 

funding

Dr. Wang’s research is funded by the National Cancer Institute and National Institute of Dental and Craniofacial Research (NIDCR).

Collaborations

Dr. Wang and his colleagues enjoy close associations with many scientists in the greater Boston area, regionally, nationally, and internationally. These include important collaborations with immunologists at the Massachusetts General Hospital; colleagues at the New England Primate Research Center; investigators at the Center for Cell and Gene Therapy of Baylor College of Medicine; head and neck oncologists at the Dana Farber Brigham and Women’s Cancer Center; and colleagues in the Department of Pathology at BWH.

Importance of Being at the Brigham

“What’s fun about working at the Brigham,” Dr. Wang offers, “ is that you can pursue your research in the science and clinical application that interests you, and at the same time have opportunities to affect patient care, such as figuring out ways to protect immunocompromised individuals from opportunistic infections and oncogenesis. Also, being part of a strong virology program at the Brigham’s Channing Laboratory and having access to so many interdisciplinary experts makes my work very fulfilling.”

Future

In the future, Dr. Wang would like to extend his translational research in EBV-related nasopharyngeal carcinoma to EBV-related Hodgkin Lymphoma, “because in this country,” Dr. Wang explains, “there are many more patients with Hodgkin Lymphoma than nasopharyngeal carcinoma. I think the challenge in Hodgkin Lymphoma is going to be even greater, because this tumor appears to use a number of different mechanisms to defend against attack by EBV-specific T cells. ”

Selected References
  1. Fogg M, Murphy JR, Lorch J, Posner M, Wang F. Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+ T cell responses in Epstein-Barr virus associated nasopharyngeal carcinoma. Virology. 2013 Jul 5;441(2):107-13. doi: 10.1016/j.virol.2013.03.016. Epub 2013 Apr 17. PubMed PMID: 23601786.
  2. Wang F. Nonhuman primate models for Epstein-Barr virus infection. Curr Opin Virol. 2013 Apr 2. doi:pii: S18796257(13)00027-8. 10.1016/j.coviro.2013.03.003. [Epub ahead of print] PubMed PMID: 23562212.
  3. Ohashi M, Fogg MH, Orlova N, Quink C, Wang F. An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection. PLoS Pathog. 2012 Dec;8(12):e1003095. doi:10.1371/journal.ppat.1003095. Epub 2012 Dec 27. PubMed PMID: 23300447; PubMed Central PMCID: PMC3531511.
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