Reversible inhibition of cytomegalovirus replication by phosphonoformate
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Abstract:
Cytomegalovirus (CMV Ad. 169)-induced late antigens are specifically inhibited by phosphonoformate (PFA). Four fresh isolates of CMV were also inhibited by PFA to varying degrees. The kinetics of CMV immediate early antigens (IEA) and early nuclear antigens (EA) produced in the presence of PFA were compared to the early phase of the replicative infection. After anticomplement immunofluorescence with anti-IEA and anti-EA, microimmunofluorometry of individual CMV-infected nuclei was performed. CMV-induced antigens had a two-wave appearance, with maxima at 6 and 24 h postinfection. The same was seen in the presence of PFA. CMV EA-containing cells persisted for more than 5 weeks in the presence of PFA, but decreased in frequency and antigen content. The inhibition of virus replication was reversible after all incubation periods assayed. After PFA release, IEA and EA appeared again in many cells, and the kinetics were similar to that of initial infection. The results suggest that the input CMV genome persists in most initially infected cells, survives PFA incubation, and is active again after PFA release. This differs from abortive CMV infections.
Insights
Phosphonoformate (PFA) inhibits Cytomegalovirus (CMV) replication by affecting antigen production. However, the CMV genome persists and reactivates after PFA removal, indicating non-abortive infection.
Area of Science:
- Virology
- Immunology
Background:
- Cytomegalovirus (CMV) is a significant human pathogen.
- Antiviral agents like phosphonoformate (PFA) are used to manage CMV infections.
Purpose of the Study:
- To investigate the effect of PFA on CMV antigen expression and replication kinetics.
- To determine if CMV infection is reversible after PFA treatment.
Main Methods:
- Anticomplement immunofluorescence assays were used to detect CMV immediate early antigens (IEA) and early nuclear antigens (EA).
- Microimmunofluorometry quantified antigen levels in individual infected nuclei.
- Kinetics of antigen appearance and persistence were analyzed with and without PFA.
Main Results:
- PFA specifically inhibited CMV-induced late antigens.
- CMV antigens appeared in two waves (6 and 24 hours post-infection), a pattern maintained in the presence of PFA.
- CMV-infected cells persisted for over 5 weeks with PFA, and viral replication resumed upon PFA removal.
Conclusions:
- The CMV genome persists in infected cells during PFA treatment.
- CMV infection is not abortive under PFA treatment and can reactivate.
- PFA's antiviral action is reversible, highlighting the dynamic nature of CMV persistence.