Identification and Sequencing of a Novel Rodent Gammaherpesvirus That Establishes Acute and Latent Infection in Laboratory Mice

Abstract

Gammaherpesviruses encode numerous immunomodulatory molecules that contribute to their ability to evade the host immune response and establish persistent, lifelong infections. As the human gammaherpesviruses are strictly species specific, small animal models of gammaherpesvirus infection, such as murine gammaherpesvirus 68 (␥HV68) infection, are important for studying the roles of gammaherpesvirus immune evasion genes in in vivo infection and pathogenesis. We report here the genome sequence and characterization of a novel rodent gammaherpesvirus, designated rodent herpesvirus Peru (RHVP), that shares conserved genes and genome organization with ␥HV68 and the primate gammaherpesviruses but is phylogenetically distinct from ␥HV68. RHVP establishes acute and latent infection in laboratory mice. Additionally, RHVP contains multiple open reading frames (ORFs) not present in ␥HV68 that have sequence similarity to primate gammaherpesvirus immunomodulatory genes or cellular genes. These include ORFs with similarity to major histocompatibility complex class I (MHC-I), C-type lectins, and the mouse mammary tumor virus and herpesvirus saimiri superantigens. As these ORFs may function as immunomodulatory or virulence factors, RHVP presents new opportunities for the study of mechanisms of immune evasion by gammaherpesviruses.A hallmark of gammaherpesvirus biology is the ability of the virus to evade the host immune response and establish persistent, lifelong infections. To accomplish this, gammaherpesviruses encode numerous molecules that enable them to escape, inhibit, or subvert multiple facets of the immune system. These immune evasion strategies include impairment of immune cell function, downregulation of antigen presentation, interference with cytokine and chemokine responses and signaling, inhibition of the complement pathway, hijacking of the DNA damage response pathway, and blockade of apoptosis and autophagy (76; reviewed in references 44 and 87). The human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are associated with several malignancies, including Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma for EBV (37, 62) and Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma for KSHV (52). Because these viruses are strictly species specific, however, it has been helpful to evaluate the contributions of virus-encoded immunomodulatory molecules to gammaherpesvirus pathogenesis using rodent models. Since the full spectrum of immune evasion strategies cannot be expected to be utilized by any single virus, it is useful to identify viruses that are experimentally manipulable, including via analysis of infection in laboratory mice, and that contain potentially novel immunomodulatory genes.Studies of in vivo gammaherpesvirus infection and pathogenesis have relied on small animal model systems, particularly the mouse pathogen murine gammaherpesvirus 68 (␥HV68; also known as MHV-68 or MuHV-4). ␥HV68 carries several immune evasio...

Newly Discovered Viral E3 Ligase pK3 Induces Endoplasmic Reticulum-associated Degradation of Class I Major Histocompatibility Proteins and Their Membrane-bound Chaperones

“…pK3 Is Viral MARCH E3 Ligase That Down-regulates Surface MHCI Protein Expression-The recent sequencing and annotation of the RHVP genome revealed the presence of multiple ORFs predicted to encode proteins involved in viral immune evasion (23). One putative immunevasin discovered in the genome of this novel ␥-herpesvirus (ORF R12) was predicted to encode a vMARCH ubiquitin ligase we designated Peru K3 (pK3).…”

“…RHVP was isolated from a lung homogenate of a pygmy rice rat, and it establishes acute and latent infections in laboratory mice. Furthermore, the recently annotated genomic sequence of RHVP contains genes conserved in ␥-herpesvirus strains and has a similar overall gene organization as ␥HV68 and KSHV (23). Of particular interest, the RHVP genome ORF R12 was also predicted to encode a unique K3 homolog (designated pK3 for Peru K3) with a signature RING-CH domain.…”

“…Furthermore, recent studies have revealed mechanistic similarities between MARCH1 regulation of MHCII proteins and kK3/kK5 regulation of MHCI proteins (22). Based on the ability of using vMARCH proteins to elucidate novel features of ubiquitin-dependent degradation pathways, we characterize here a novel vMARCH homolog from the newly discovered and sequenced virus rodent herpesvirus Peru (RHVP) (23). RHVP was isolated from a lung homogenate of a pygmy rice rat, and it establishes acute and latent infections in laboratory mice.…”

Detection of Transcripts and an Infectious Dose of Murine Gammaherpesvirus 68 in Dermacentor reticulatus Ticks

“…Epidemiological surveys in the UK, Germany, France, and Peru found several other gammaherpesviruses in free-living rodents [3][4][5][6]. Although it has been documented that MHV-68 is mainly transmitted in the rodent population via intranasal routes and through body fluids, such as saliva, urine, tears, and breast milk, it is not yet fully understood how this virus spreads in nature.…”

Specific Mutation of a Gammaherpesvirus-Expressed Antigen in Response to CD8 T Cell SelectionIn Vivo

“…Briefly, genomic DNA for each virus was prepared as previously described (25) and sequenced on the 454 GS-FLX platform (454 Life Sciences) according to the manufacturer's instructions. For each virus, randomly selected sets containing different numbers of sequence reads were assembled using Newbler as previously described (16) and the largest contig generated is reported here. The estimated fold coverage for each assembled genome was as follows: for ␥HV68.OVA.1, 42-fold; for ␥HV68.OVA.2, 53-fold; for ␥HV68.OVA.3, 52-fold; for ␥HV68.OVA.5, 41-fold; for ␥HV68.OVA.6, 12-fold; for ␥HV68.OVA.7, 11-fold; and for ␥HV68.OVA.9, 10-fold.…”