Murine gammaherpesvirus 68 cyclin D homologue is required for efficient reactivation from latency

Murine gammaherpesvirus 68 (MHV68) is a gammaherpesvirus that was first iso lated from murid rodents, MHV68 establishes a latent infection in the splee n and other lymphoid organs. Several gammaherpesviruses, including herpesvi rus saimiri, human herpesvirus 8, and MHV68, encode proteins with extensive homolog to the D-type cyclins. To study the function of the cyclin homolog ue, a recombinant MHV68 has been constructed that lacks the cyclin homologu e and expresses P-galactosidase as a marker (MHV68(cy-)). MHV68(cy-) grows in vitro with kinetics and to titers similar to those of the wild type. BAL B/c mice infected with mixtures of equivalent amounts of the wild type and MHV68(cy-) show deficient growth of the MHV68(cy-) in an acute infection. I nfection of SCID mice with virus mixtures also showed decreased MHV68(cy-) virus growth, indicating that the deficiency is not mediated by T or B cell s. Although mice infected with mixtures containing 100 times as much MHV68( cy-) had greater splenic titers of the mutant virus than wild-type virus in acute infection, at 28 days postinfection splenocytes from these mice reac tivated primarily wild-type virus. Quantitative PCR data indicate that equi valent genomes were present in the latent state, Reinsertion of the cyclin homologue into the cyclindeleted virus restored the wild-type phenotype. Th ese results indicate that the MHV68 cyclin D homologue mediates important f unctions in the acute infection and is required for efficient reactivation from latency.