Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus

• Published in: Journal of virology Vol. 90; no. 6; pp. 2818 - 2829
• Main Authors: Mboko, Wadzanai P, Olteanu, Horatiu, Ray, Avijit, Xin, Gang, Darrah, Eric J, Kumar, Suresh N, Kulinski, Joseph M, Cui, Weiguo, Dittel, Bonnie N, Gauld, Stephen B, Tarakanova, Vera L
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 15-03-2016
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - virology; Cell Transformation, Viral; Gammaherpesvirinae - immunology; Germinal Center - immunology; Germinal Center - virology; Host-Pathogen Interactions; Humans; Interferon Regulatory Factor-1 - metabolism; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Pathogenesis and Immunity; Spleen - immunology; Spleen - pathology; Spleen - virology
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/jvi.02774-15

Gammaherpesviruses are ubiquitous pathogens that are associated with the development of B cell lymphomas. Gammaherpesviruses employ multiple mechanisms to transiently stimulate a broad, polyclonal germinal center reaction, an inherently mutagenic stage of B cell differentiation that is thought to be the primary target of malignant transformation in virus-driven lymphomagenesis. We found that this gammaherpesvirus-driven germinal center expansion was exaggerated and lost its transient nature in the absence of interferon-regulatory factor 1 (IRF-1), a transcription factor with antiviral and tumor suppressor functions. Uncontrolled and persistent expansion of germinal center B cells led to pathological changes in the spleens of chronically infected IRF-1-deficient animals. Additionally, we found decreased IRF-1 expression in cases of human posttransplant lymphoproliferative disorder, a malignant condition associated with gammaherpesvirus infection. The results of our study define an unappreciated role for IRF-1 in B cell biology and provide insight into the potential mechanism of gammaherpesvirus-driven lymphomagenesis.
Gammaherpesviruses establish lifelong infection in most adults and are associated with B cell lymphomas. While the infection is asymptomatic in many hosts, it is critical to identify individuals who may be at an increased risk of virus-induced cancer. Such identification is currently impossible, as the host risk factors that predispose individuals toward viral lymphomagenesis are poorly understood. The current study identifies interferon-regulatory factor 1 (IRF-1) to be one of such candidate host factors. Specifically, we found that IRF-1 enforces long-term suppression of an inherently mutagenic stage of B cell differentiation that gammaherpesviruses are thought to target for transformation. Correspondingly, in the absence of IRF-1, chronic gammaherpesvirus infection induced pathological changes in the spleens of infected animals. Further, we found decreased IRF-1 expression in human gammaherpesvirus-induced B cell malignancies.