Murine Gammaherpesvirus 68 ORF48 Is an RTA-Responsive Gene Product and Functions in both Viral Lytic Replication and Latency during In Vivo Infection. –

Murine Gammaherpesvirus 68 ORF48 Is an RTA-Responsive Gene Product and Functions in both Viral Lytic Replication and Latency during In Vivo Infection. -

Numerous studies have shown that NK cells are important in controlling the early stages of infection with alpha- or betaherpesviruses. Recently, TLR signaling via MyD88 has been reported to play an important function in development of a B-cell response. Murine gammaherpesvirus 68 (MHV-68) provides a tractable model to define common, conserved features of gammaherpesvirus biology. Prolonged infection revealed a range of outcomes, from spontaneous regression to pulmonary lymphoma. Here, we demonstrate that XBP-1 is capable of trans-activating the murine gammaherpesvirus 68 (MHV68) RTA promoter in vitro, consistent with previous observations for EBV and KSHV. Mutagenesis of 48pRRE in the context of the viral genome demonstrated that the expression of ORF48 is activated by RTA through 48pRRE during de novo infection. These results (i) confirm that MHV-76 is the only non-oncogenic murine gammaherpesvirus of all the so far tested ones, (ii) suggest that some of the genes deleted in MHV-76 might be responsible for the oncogenicity of murine gammaherpesviruses, (iii) confirm that viral ORF73 is one of major latency-associated genes that is suppressed during virus reactivation, and (iv) present MHV-76 as another murine gammaherpesvirus useful as a model for study of gammaherpesvirus pathogenesis, oncogenicity, latency and reactivation.
Murine Gammaherpesvirus 68 ORF48 Is an RTA-Responsive Gene Product and Functions in both Viral Lytic Replication and Latency during In Vivo Infection. -

Pulse-chase analysis and endoglycosidase-H digestion showed that the 130,000-molecular-weight form was a precursor of the 150,000-molecular-weight form, and cell surface labelling showed that the 150,000-molecular-weight form alone was on the cell surface. These results show that mucosal epithelia can act as a nonlymphoid reservoir for gammaherpesvirus persistence, and that there is a two-way movement of virus between lymphoid and nonlymphoid compartments during persistence. Reinsertion of the cyclin homologue into the cyclin-deleted virus restored the wild-type phenotype. The replication and transcription activator (RTA), conserved among gammaherpesviruses, serves as a molecular switch for the virus life cycle. It works as a transcriptional regulator to activate the expression of many viral lytic genes. However, only a limited number of such downstream genes have been uncovered for MHV-68. We began our study by exploring whether γHV68 infection in healthy mice could sustain the long-term production of autoantibodies and induce other symptoms of autoimmunity.

By constructing a mutant virus that is deficient in ORF48 expression and through infection of laboratory mice, we showed that ORF48 plays important roles in different stages of viral infection in vivo. Our study provides insights into the transcriptional regulation and protein function of MHV-68, a desired model for studying gammaherpesviruses.

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