Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection
Gammaherpesviruses are oncogenic pathogens that establish lifelong infections. There are no FDA-approved vaccines against Epstein–Barr virus or Kaposi sarcoma herpesvirus. Murine gammaherpesvirus-68 (MHV68) infection of mice provides a system for investigating gammaherpesvirus pathogenesis and testi...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/16/12/1930 |
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| Summary: | Gammaherpesviruses are oncogenic pathogens that establish lifelong infections. There are no FDA-approved vaccines against Epstein–Barr virus or Kaposi sarcoma herpesvirus. Murine gammaherpesvirus-68 (MHV68) infection of mice provides a system for investigating gammaherpesvirus pathogenesis and testing vaccine strategies. Prime-boost vaccination with a replication-dead virus (RDV) that does not express the essential replication and transactivator protein (RTA) encoded by <i>ORF50</i> (RDV-50.stop) protected against WT virus replication and reduced latency in C57BL/6 mice, and prevented lethal disease in <i>Ifnar1</i><sup>−/−</sup> mice. To further improve the RDV vaccine and more closely model KSHV vaccine design, we generated an RDV lacking the unique M1-M4 genes and the non-coding tRNA-miRNA-encoded RNAs (TMERs) 6, 7, and 8 that collectively promote latency of MHV68 in vivo. Prime-boost vaccination of mice with RDV-50.stop∆M1-M4 elicited neutralizing antibodies and virus-specific CD8 T-cell responses in the lungs and spleens, the respective sites of acute replication and latency, that were comparable to RDV-50.stop vaccination. When challenged with WT MHV68, vaccinated mice exhibited a near-complete block of lytic replication and a reduction in latency and reactivation. We conclude that the unique M1-M4 genes and TMERs 6, 7, and 8, which are major determinants of WT MHV68 pathogenesis, are not required for eliciting protective immunity. |
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| ISSN: | 1999-4915 |