A gammaherpesvirus 68 gene 50 null mutant establishes long-term latency in the lung but fails to vaccinate against a wild-type virus challenge.
The gammaherpesvirus immediate-early genes are critical regulators of virus replication and reactivation from latency. Rta, encoded by gene 50, serves as the major transactivator of the lytic program and is highly conserved among all the gammaherpesviruses, including Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and murine gammaherpesvirus 68 (gammaHV68). Introduction of a translation stop codon in gammaHV68 gene 50 (gene 50.stop gammaHV68) demonstrated that Rta is essential for virus replication in vitro. To investigate the role that virus replication plays in the establishment and maintenance of latency, we infected mice with gene 50.stop gammaHV68. Notably, the gene 50.stop virus established a long-term infection in lung B cells following intranasal infection of mice but was unable to establish latency in the spleen. This complete block in the establishment of latency in the spleen was also seen when lytic virus production was inhibited by treating mice infected with wild-type virus with the antiviral drug cidofovir, implicating virus replication and not an independent function of Rta in the establishment of splenic latency. Furthermore, we showed that gene 50.stop gammaHV68 was unable to prime the immune system and was unable to protect against a challenge with wild-type gammaHV68, despite its ability to chronically infect lung B cells. These data indicate gammaherpesviruses that are unable to undergo lytic replication in vivo may not be viable vaccine candidates despite the detection of cells harboring viral genome at late times postinfection.
Moser
Janice M
JM
Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, Emory University School of Medicine, 954 Gatewood Road NE, Atlanta, GA 30329, USA.
Farrell
Michael L
ML
Krug
Laurie T
LT
Upton
Jason W
JW
Speck
Samuel H
SH
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D000077404:Cidofovir; D018388:Codon, Terminator; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D005814:Genes, Viral; D022283:Herpesvirus Vaccines / Q000235:genetics / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology; D018144:Rhadinovirus / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D015534:Trans-Activators / Q000235:genetics; D014611:Vaccination; D014764:Viral Proteins / Q000235:genetics; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D018388:Codon, Terminator; D022283:Herpesvirus Vaccines; D063065:Organophosphonates; D015534:Trans-Activators; D014764:Viral Proteins; D003596:Cytosine; D000077404:Cidofovir