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

Abstract

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. IMPORTANCE 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 Interferon-regulatory factor 1 (IRF-1) is a conserved transcription factor that restricts the replication of diverse RNA and DNA viruses in vitro via a poorly understood mechanism (1, 2). Additionally, IRF-1 suppresses replication and restricts the tropism of West Nile virus (WNV) (3), vesicular stomatitis virus (VSV) (4), and murine norovirus (5) during the acute phase of infection in vivo. However, there is a paucity of studies defining the role of IRF-1 during chronic virus infection. Such a role undoubtedly exists, as distinct IRF-1 polymorphisms are associated with either susceptibility to chronic hepatitis B and C virus infection (6) or resistance to HIV-1 (7). Additionally, IRF-1 is a tumor suppressor, as evidenced by the synergy between IRF-1 insufficiency and oncogene deregulation in animal models (8) and decreased IRF-1 expression in several human cancers (9). Importantly, this tumor suppressor nature of IRF-1 may be of particular relevance in the context of chronic infection with cancer-associated viruses.Our study focuses on the interaction between IRF-1 and gammaherpesviruses, ubiquitous pathogens that establish lifelong infection in a majority of the human population and are associated with the development of B cell lymphomas (10). In spite of the widespread nature of gammaherpesvirus infection, the host risk factors that predispose individuals toward gammaherpesvirus-driven lymphomagenesis are still poorly understood. Gammaherpesviruses establish long-term latency in memory B cells. Accordingly, these viruses employ both viral and host mechanisms to stimulate a germinal cent...

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

“…This suggests that, at least during acute MHV68 infection, IRF-1 functions are complemented by type I IFN expression and signaling. In contrast, we showed that IRF-1 Ϫ/Ϫ mice have poor control of chronic MHV68 infection (23), indicating that type I IFN signaling is no longer able to compensate for IRF-1 deficiency once gammaherpesvirus infection becomes chronic. (33).…”

Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction

“…In contrast to the positive role of IRF8 in EBV lytic replication observed in our study, most of the IRFs contribute to anti-viral immunity and block the infection or lytic reactivation of herpesviruses. For example, it was reported that IRF1 restricts gammaherpesvirus replication through IFN-mediated suppression of viral replication [ 73 , 74 , 75 , 76 ]. IRF2 also suppresses gammaherpesvirus replication and reactivation by inhibiting the M2 gene promoter [ 77 ].…”

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

“…The elucidation of oncoprotein-mediated inhibition of transactivating IRF activity during HPV infection has reinforced the conceived supposition that immune response and viral immune evasion may be intimately tied to cancer (Park et al, 2000; Ronco et al, 1998; Um et al, 2002). IRF-1 has been characterized as a tumor suppressor based on the presence of low IRF-1 levels in a number of human cancers, its function in promoting apoptosis and suppressing cell proliferation in vitro , as well as the correlation between loss of IRF-1 and oncogene deregulation in vivo (Mboko et al, 2016; Nozawa et al, 1999; Savitsky et al, 2010). Furthermore, epidemiological studies have proposed that viral evasion factors of cellular immunity can be etiological agents of oncogenesis (Um et al, 2002).…”