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Use of temperature-sensitive mutants of mouse cytomegalovirus as vaccines
1Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Abstract:
Three temperature-sensitive (ts) mutants of mouse cytomegalovirus (MCMV) were compared with parent virus for their ability to produce acute infection, to stimulate protection against a lethal challenge with salivary gland MCMV, and to become latent and then be reactivated. During the acute phase of infection, ts mutant virus demonstrated very limited replication. During the later phase of infection (seven to 14 days after challenge), titers of virus in the pancreas and salivary glands in mice infected with parent virus continued to rise, whereas no virus could be detected in mice infected with the ts mutants. Prior infection with parent virus or the ts mutants protected susceptible mice from a lethal dose of salivary gland MCMV. One year after infection, treatment of mice with an immunosuppressive regimen resulted in reactivation of parent and ts mutant virus. Reactivated virus recovered from mice infected with ts mutant virus remained temperature sensitive.
Insights
Temperature-sensitive (ts) mouse cytomegalovirus (MCMV) mutants showed limited replication but still provided protection against lethal MCMV challenge. These ts mutants could also establish latent infections and reactivate, retaining their temperature-sensitive properties.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Mouse cytomegalovirus (MCMV) is a significant pathogen, and understanding its replication, latency, and reactivation is crucial for developing effective vaccines and therapies.
- Temperature-sensitive (ts) mutants offer a potential avenue for live attenuated vaccines due to their conditional replication defects.
Purpose of the Study:
- To evaluate the in vivo behavior of three ts MCMV mutants compared to wild-type MCMV.
- To assess the ability of ts MCMV mutants to induce protective immunity and establish latent infections.
- To determine if reactivated ts MCMV mutants retain their temperature-sensitive phenotype.
Main Methods:
- Infection of mice with ts MCMV mutants and parent MCMV.
- Monitoring viral replication during acute infection.
- Assessing protection against lethal MCMV challenge after prior infection.
- Inducing reactivation from latency using immunosuppression.
- Characterizing the temperature sensitivity of reactivated viruses.
Main Results:
- Ts MCMV mutants exhibited significantly reduced replication during the acute phase of infection.
- No detectable virus was found in the pancreas and salivary glands of mice infected with ts mutants in the later stages of infection.
- Infection with either parent MCMV or ts MCMV mutants conferred protection against a lethal MCMV challenge.
- Both parent MCMV and ts MCMV mutants were successfully reactivated from latency following immunosuppression one year post-infection.
- Reactivated ts MCMV mutants maintained their temperature-sensitive characteristics.
Conclusions:
- Ts MCMV mutants are attenuated in replication but can still induce protective immunity.
- Ts MCMV mutants establish persistent, latent infections that are capable of reactivation.
- The temperature-sensitive phenotype is stable through latency and reactivation, supporting their potential as vaccine candidates.