CAREER: Murine Gammaherpesvirus 68 Persistence and Interaction With Host Chemokine Networks

University Of Southern Maine, Portland ME

Investigators

Abstract

CAREER Award: Murine gammaherpesvirus 68 persistence and interaction with host chemokine networks. The evolutionary interactions of viruses and their hosts reflect diverse adaptive strategies. Herpesviruses exemplify a co-evolutionary strategy in which host innate and adaptive immune defenses and cellular signalling are balanced by virus induced modulations that typically result in an altered homeostasis facilitating permanent association of the virus and the multicellular host. While this balance is maintained, there is usually little cost in fitness for the host. The large DNA genomes of herpesviruses encode numerous accessory genes unnecessary for viral replication but critically involved in virus persistence through modulation of host responses. Gammaherpesviruses, which are capable of persistence in lymphoid cells, contain a particularly impressive variety of genes apparently acquired through molecular piracy of host genes relevant to immune recognition and response, cell cycle control, complement-mediated killing, and apoptotic responses. Prominent within the genetic repertoire of gamma-2-herpesviruses (or rhadinoviruses) are genes encoding products that interact with host chemokine networks which are critical in regulation of cell traffic under both homeostatic and inflammatory conditions. Conserved within several rhadinovirus genomes is a G-protein-coupled receptor (GPCR) gene encoding a putative CXC-chemokine receptor homolog most closely related to CXCR2. Studies of gammaherpesvirus latency and persistence together with functional analysis of the viral CXC chemokine receptor encoded by ORF74 of murine gammaherpesvirus 68 (MHV-68) will be pursued in these studies with extensive student participation. Interaction of MHV-68 with murine hosts is highly accessible to investigation using powerful genetic tools making this system ideally suited for advancing understanding of gammaherpesvirus biology including mechanisms of gammaherpesvirus latency and persistence. The MHV-68 genome has been fully sequenced and can be manipulated using conventional in vitro recombination methods. Availability of genetically defined mouse strains (including transgenic strains and those with specific gene knockouts) affords unparalleled opportunities to query the nature of the virus-host association using manipulations of both virus and host genetics. These investigations of MHV-68 persistence and interaction with host chemokine networks will exploit the advantages of this virus-host system. The intriguing nature of known gammaherpesvirus-host interactions, the elegance of appropriate experimental methods including those that are standard to molecular biology, and the abundance of unanswered questions together provide a research framework that is well suited for integration into educational activities involving graduate students, undergraduates, and pre-college students and their teachers. Studies of cloned MHV-68 genes using common molecular biological methods will continue to provide an inquiry-based context for introductory and advanced molecular biology laboratory courses. Drawing upon the extensive experience of the principal investigator in construction of recombinant rhadinoviruses for study of gene function within the viral context, graduate student projects will include construction of MHV-68 recombinants useful for understanding virus-host interactions. Both graduate and undergraduate students will perform studies of MHV-68 gene function in vitro using cloned viral gene expression constructs. Ongoing interactions with regional high school students and their teachers will provide opportunities for selected students to participate in small, well defined laboratory research projects utilizing basic molecular biological methods.