Gammaherpesviruses establish life-long infection in a majority of humans worldwide and are associated with the development of cancer, including B cell lymphomas. The intimate relationship between gammaherpesviruses and B cell differentiation is directly linked to the lymphomagenic capacity of these viruses. To ensure the establishment of long-term latency in memory B cells, gammaherpesviruses drive a unique polyclonal germinal center reaction during early infection. Germinal center reaction represents a stage of B cell differentiation that is characterized by rapid division of activated B cells along with genetic instability driven by enzymes that either induce DNA breaks or mutagenize DNA. It is not surprising that most Epstein-Barr virus-driven B cell lymphomas originate from germinal center or post germinal center B cells. This robust, gammaherpesvirus-stimulated germinal center reaction is transient and returns to near-baseline levels in long-term infected hosts. Importantly, it is not clear what attenuates gammaherpesvirus-driven germinal center reaction. We have identified Interferon Regulatory Factor-1 (IRF-1) as the first host factor that specifically attenuates gammaherpesvirus-driven germinal center reaction. Studies proposed here test the hypothesis that IRF-1 is the critical host factor that attenuates gammaherpesvirus-driven expansion and transformation of germinal center B cells throughout life-long infection. The proposed studies will define IRF-1-mediated signaling changes that attenuate gammaherpesvirus-driven expansion of germinal center response and the relative contributions of B- and T cell-intrinsic functions of IRF-1 to this process. Further, proposed studies will develop a novel animal model of gammaherpesvirus lymphomagenesis. Successful completion of the proposed studies will offer insights into the tumor suppressor mechanisms of IRF-1 and generate novel animal models that will be of value to infectious disease, immunology, and cancer fields.

Public Health Relevance

Gammaherpesviruses infect a majority of adults and this infection can lead to virus-driven B cell lymphomas. Our preliminary studies identified a host transcription factor that is likely to oppose virus-driven lymphomagenesis. Successful completion of the proposed studies will determine how this host transcription factor opposes viral processes to restrict virus infection and, possibly, virus-driven cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA203923-02
Application #
9393312
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2016-12-05
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Darrah, Eric J; Kulinski, Joseph M; Mboko, Wadzanai P et al. (2017) B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection. J Virol 91:
Mboko, Wadzanai P; Rekow, Michaela M; Ledwith, Mitchell P et al. (2017) Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection. J Virol 91:
Darrah, Eric J; Stoltz, Kyle P; Ledwith, Mitchell et al. (2017) ATM supports gammaherpesvirus replication by attenuating type I interferon pathway. Virology 510:137-146