DETERMINANTS OF CHRONIC GAMMAHERPESVIRUS 68 INFECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gammaherpesviruses establish life-long, latent infections in host lymphocytes during which a limited subset of viral genes facilitate viral maintenance. ORF73 is a conserved gammaherpesvirus gene whose product was demonstrated for Kaposi?s sarcoma-associated herpesvirus to tether viral genomes to host chromosomes and interfere with cellular homeostatic regulatory pathways. To understand the role of ORF73 in the establishment and maintenance of ?HV68 latent infection in vivo, we utilized targeted mutants to define ORF73 as critical to the establishment of a latent infection following intranasal inoculation. In addition, ORF73 mutants exhibited a severe replication defect in the lungs of infected mice. Analysis of viral replication in primary murine embryonic fibroblasts revealed that lytic replication of ORF73 mutant virus is impaired in culture. Further, this replication deficit correlates with inhibition of host translation and increased kinetics of apoptosis in infected cells. These findings suggest a role for ORF73 in limiting host-cell death to promote efficient viral replication and dissemination that facilitates the establishment of ?HV68 latent infection.