COMPLETE SEQUENCE AND GENOMIC ANALYSIS OF MURINE GAMMAHERPESVIRUS-68

Murine gammaherpesvirus 68 (gamma HV68) infects mice, thus providing a tractable small-animal model for analysis of the acute and chronic pa thogenesis of gammaherpesviruses. To facilitate molecular analysis of gamma HV68 pathogenesis, we have sequenced the gamma HV68 genome, The genome contains 118,237 bp of unique sequence flanked by multiple copi es of a 1,213-bp terminal repeat, The GC content of the unique portion of the genome is 46%, while the GC content of the terminal repeat is 78%. The unique portion of the genome is estimated to encode at least 80 genes and is largely colinear with the genomes of Kaposi's sarcoma herpesvirus (KSHV; also known as human herpesvirus 8), herpesvirus sai miri (HVS), and Epstein Barr virus (EBV). We detected 63 open reading frames (ORFs) homologous to HVS and KSHV ORFs and used the HVS/KSHV nu mbering system to designate these ORFs, gamma HV68 shares with HVS and KSHV ORFs homologous to a complement regulatory protein (ORF 4), a D- type cyclin (ORF 72), and a G-protein-coupled receptor with close homo logy to the interleukin-8 receptor (ORF 74), One ORF (K3) was identifi ed in gamma HV68 as homologous to both ORFs K3 and K5 of KSHV and cont ains a domain found in a bovine herpesvirus 1 major immediate-early pr otein, We also detected 16 methionine initiated ORFs predicted to enco de proteins at least 100 amino acids in length that are unique to gamm a HV68 (ORFs M1 to 14), ORF M1 has striking homology to poxvirus serpi ns. while ORF M11 encodes a potential homolog of Bcl-2-like molecules encoded by other gammaherpesviruses (gene 16 of HVS and KSHV and the B HRF1 gene of EBV), In addition, clustered at the left end of the uniqu e region are eight sequences with significant homolog to bacterial tRN As, The unique region of the genome contains two internal repeats: a 4 0-bp repeat located between bp 26778 and 28191 in the genome and a 100 -bp repeat located between bp 98981 and 101170, Analysis of the gamma HV68, HVS, EBV, and KSHV genomes demonstrated that each of these virus es have large colinear gene blocks interspersed by regions containing virus-specific ORFs, Interestingly, genes associated with EBV cell tro pism, latency, and transformation are all contained within these regio ns encoding virus-specific genes, This finding suggests that pathogene sis-associated genes of gammaherpesviruses, including gamma HV68 may b e contained in similarly positioned genome regions, The availability o f the gamma HV68 genomic sequence will facilitate analysis of critical issues in gammaherpesvirus biology via integration of molecular and p athogenetic studies in a small-animal model.