Human cytomegalovirus virion-associated mRNA as a marker of productive
infection in immunocompromised patients.
Abstract
Human Cytomegalovirus (HCMV) transcripts (including UL21.5 mRNA) have
been found to be packaged in virions and their detection in plasma may
indicate the presence of infectious viral particles. Objective of this
study was to verify whether UL21.5 mRNA detected in the plasma was
indeed encapsulated in viral particles, representing an indirect marker
of active replication. To distinguish between virion-packaged and
free-floating RNA, plasma samples from 22 immunocompromised patients
were tested before and after ribonuclease (RNAse) digestion. UL21.5 mRNA
was detected 1-2 weeks prior to preemptive therapy administration in 20
episodes (from 18 patients) of clinically significant DNAemia, while it
was undetectable in three of the four patients with transient,
self-resolving DNAemia. After RNAse digestion, UL21.5 mRNA was still
detectable, with a median reduction of 0.1 (IQ range 0-0.3) Log
10. Concentrations of UL21.5 mRNA in plasma correlated
significantly with HCMV DNA in whole blood or plasma (R=0.67), and 75%
of samples positive for UL21.5 mRNA had HCMV DNA concentrations above 10
4 copies/ml blood or 10 3 copies/ml
plasma. Moreover, UL21.5 mRNA was positive in patients who developed
HCMV infection resistant to letermovir or maribavir, whereas it was
undetectable in plasma of patients with transient self-resolving DNAemia
blips during letermovir prophylaxis (not associated with
drug-resistance). HCMV UL21.5 mRNA in plasma is virion-associated and
represents a marker for productive HCMV infection. The determination of
UL21.5 mRNA could improve current strategies for the management of HCMV
infection in immunocompromised patients.