Herpesviruses are forever. They are a large family of viruses that share the ability to establish a lifelong latent infection within their hosts. The latent infection is controlled by the host immune system: immunosuppression results in reactivation of lytic infection. A hallmark of the gammaherpesviruses is their ability to establish latent infection within the lymphoid system of the host. Gammaherpesviruses persist for life within cells of the immune system, the very system responsible for their clearance. This balance between the host immune system and viral latency is complex and is dependent on both host and viral genes. The gammaherpesviruses include the human pathogens Epstein Barr virus and Kaposi's sarcoma associated herpesvirus (KSHV), as well as murine gammaherpesvirus 68 (γHV68). Each of these viruses use B lymphocytes as a major reservoir of latency and are associated with B cell malignancies.
The focus of my lab is on gammaherpesvirus pathogenesis, particularly on virus and host mechanisms to regulate latency and reactivation.
The availability of γHV68 as a murine model of gammaherpesvirus pathogenesis provides the following benefits: 1) a genetically manipulable virus, 2) a genetically manipulable host system with a wealth of genetic alterations and strain variations, and 3) the ability to study pathogen/host interactions over the entire course of viral infection.
ΓHV68 and KSHV both encode homologs of the host cyclins. Exogenous expression of the viral cyclins promotes cell cycle progression and leads to cellular transformation. Infection of normal mice with a mutant γHV68 deficient in viral cyclin expression (v-cyclin KO) is equivalent to wild-type virus in lytic infection, but results in a profound defect in reactivation from latency and associated chronic disease. The mechanism of viral cyclin action in maintenance and reactivation from latency is being investigated by use of in vivo complementation and molecular biological studies. The viral cyclins interact with host tumor suppressor proteins, including the retinoblastoma protein and the cyclin dependent kinase inhibitor, p18Ink4c. The relationship between tumor suppressors and virus infection is being investigated at the level of both whole animal and molecular interactions.
The gammaherpesviruses establish latency in B lymphocytes, and virally transformed cells demonstrate altered B cell signaling. It is thought that this ability to derail B cell signaling is important to establishment of latency and evasion of host immune detection. One of the means by which gammaherpesviruses may control infected host cells is by virus encoded miRNAs. Our lab is investigating the role of viral miRNAs on cell cycle and signaling of infected host B cells. Finally, the role of host B cell signaling in establishment of latency is being investigated by infection of mice and cell lines deficient in particular B cell signaling components.