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. Herpesviruses are subdivided by genomic and biological properties. A hallmark of the gammaherpesviruses is their ability to establish latent infection within the lymphoid system of the host. Gammaherpesviruses persist for a lifetime 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 (gHV68). 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 gHV68 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.
gHV68 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 gHV68 deficient in viral cyclin expression (v-cyclin KO) is equivalent to wild-type virus in all parameters of lytic infection, but results in a profound defect in reactivation from latency. Infection of B cell-deficient mice with this v-cyclin KO results in failure to maintain lifelong latency (the hallmark of herpesviruses). 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 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. 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.