Complete sequence and genomic analysis of murine gammaherpesvirus 68

Abstract

Murine gammaherpesvirus 68 (␥HV68) infects mice, thus providing a tractable small-animal model for analysis of the acute and chronic pathogenesis of gammaherpesviruses. To facilitate molecular analysis of ␥HV68 pathogenesis, we have sequenced the ␥HV68 genome. The genome contains 118,237 bp of unique sequence flanked by multiple copies 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 saimiri (HVS), and Epstein-Barr virus (EBV). We detected 63 open reading frames (ORFs) homologous to HVS and KSHV ORFs and used the HVS/KSHV numbering system to designate these ORFs. ␥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 homology to the interleukin-8 receptor (ORF 74). One ORF (K3) was identified in ␥HV68 as homologous to both ORFs K3 and K5 of KSHV and contains a domain found in a bovine herpesvirus 4 major immediate-early protein. We also detected 16 methionine-initiated ORFs predicted to encode proteins at least 100 amino acids in length that are unique to ␥HV68 (ORFs M1 to 14). ORF M1 has striking homology to poxvirus serpins, while ORF M11 encodes a potential homolog of Bcl-2-like molecules encoded by other gammaherpesviruses (gene 16 of HVS and KSHV and the BHRF1 gene of EBV). In addition, clustered at the left end of the unique region are eight sequences with significant homology to bacterial tRNAs. The unique region of the genome contains two internal repeats: a 40-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 ␥HV68, HVS, EBV, and KSHV genomes demonstrated that each of these viruses have large colinear gene blocks interspersed by regions containing virus-specific ORFs. Interestingly, genes associated with EBV cell tropism, latency, and transformation are all contained within these regions encoding virus-specific genes. This finding suggests that pathogenesis-associated genes of gammaherpesviruses, including ␥HV68, may be contained in similarly positioned genome regions. The availability of the ␥HV68 genomic sequence will facilitate analysis of critical issues in gammaherpesvirus biology via integration of molecular and pathogenetic studies in a small-animal model.

Complement and viral pathogenesis

“…One mechanism employed by viruses is to directly encode proteins that have structural and functional homology to host proteins that function as regulators of complement activation. Gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, herpesvirus saimiri, and murine γ-herpesvirus 68 (γHV68) encode homologs of complement regulatory proteins (Albrecht and Fleckenstein, 1992;Mullick et al, 2003a;Spiller et al, 2003;Virgin et al, 1997). The γHV68 regulator of complement activation (RCA) protein is expressed on the surfaces of infected cells and is detected in supernatants of γHV68infected cells, thus it has both membrane-associated and soluble forms (Kapadia et al, 1999).…”

Global mRNA Degradation during Lytic Gammaherpesvirus Infection Contributes to Establishment of Viral Latency

“…Gammaherpesviruses include the human pathogens Epstein-Barr virus (EBV/HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) [8], the etiologic agents of some of the most common AIDS-associated cancers, such as Burkitt's lymphoma, nasopharyngeal carcinoma, and primary effusion lymphoma. The related murine gammaherpesvirus 68 (MHV68) is often used as a model for human gammaherpesviruses because, unlike KSHV and EBV, it is genetically tractable, readily replicates in tissue culture without the use of chemicals or overexpression to overcome latency, and infects small rodents including laboratory mice [9,10,11]. MHV68 has therefore been instrumental in the identification of factors that contribute to in vivo replication and pathogenesis of the gammaherpesviruses.…”

A Gammaherpesvirus Ubiquitin-Specific Protease Is Involved in the Establishment of Murine Gammaherpesvirus 68 Infection

“…MHV-68 is a natural rodent pathogen (5) and readily infects laboratory C57/BL6 mice. The genome of MHV-68 has been sequenced and shows a close genetic relationship to the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and EBV (39). The functions of many MHV-68 gene products are similar to the corresponding gene products of human gammaherpesviruses, and therefore MHV-68 is widely used as a model for the pathogenesis of gammaherpesviruses.…”