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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2024-12-01
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| author | Dipanwita Mitra Darby G. Oldenburg J. Craig Forrest Laurie T. Krug |
| author_facet | Dipanwita Mitra Darby G. Oldenburg J. Craig Forrest Laurie T. Krug |
| author_sort | Dipanwita Mitra |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-36aec8d877ff446c941d86d95bc23adf |
| institution | DOAJ |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj-art-36aec8d877ff446c941d86d95bc23adf2025-08-20T02:56:55ZengMDPI AGViruses1999-49152024-12-011612193010.3390/v16121930Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus InfectionDipanwita Mitra0Darby G. Oldenburg1J. Craig Forrest2Laurie T. Krug3HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USAGundersen Medical Foundation: Virology Research, La Crosse, WI 54601, USADepartment of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USAHIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USAGammaherpesviruses 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.https://www.mdpi.com/1999-4915/16/12/1930gammaherpesvirusMHV68vaccinereplication-dead viruslatency establishmentreactivation |
| spellingShingle | Dipanwita Mitra Darby G. Oldenburg J. Craig Forrest Laurie T. Krug Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection Viruses gammaherpesvirus MHV68 vaccine replication-dead virus latency establishment reactivation |
| title | Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection |
| title_full | Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection |
| title_fullStr | Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection |
| title_full_unstemmed | Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection |
| title_short | Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection |
| title_sort | vaccination with a replication dead murine gammaherpesvirus lacking viral pathogenesis genes inhibits wt virus infection |
| topic | gammaherpesvirus MHV68 vaccine replication-dead virus latency establishment reactivation |
| url | https://www.mdpi.com/1999-4915/16/12/1930 |
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