Hcmv-miR-UL22A-5p: A Biomarker in Transplantation With Broad Impact on Host Gene Expression and Potential Immunological Implications

Abstract

Cytomegalovirus (CMV) encodes multiple microRNAs. While these have been partially characterized in vitro, their relevance to clinical CMV infection has not been evaluated. We analyzed samples from a cohort of solid organ transplant patients with CMV disease (n = 245) for viral microRNA expression. Several CMV microRNAs were readily detectable in patients with CMV disease in variable relative abundance. Expression level generally correlated with DNA viral load and the absence of viral microRNA was associated with faster viral clearance. Detection of hcmv-miR-UL22A-5p at baseline independently predicted the recurrence of CMV viremia upon discontinuation of antiviral therapy (OR 3.024, 95% CI: 1.35-6.8; p = 0.007). A combination of direct mRNA targeting by the microRNA and indirect modulation of gene expression involving isoforms of the transcriptional regulator C-MYC may be responsible for the broad effects seen in the association of gene transcripts with the RNA-induced silencing complex and in global protein expression upon hcmv-miR-UL22A-5p transfection. This novel study of in vivo viral microRNA expression profiles provides unique insight into the complexity of clinical CMV infection following transplantation. We provide evidence that viral microRNAs may have complex effects on gene expression and be associated with specific virologic and clinical outcomes, and thus could be further evaluated as biomarkers.

Manipulation of Viral MicroRNAs as a Potential Antiviral Strategy for the Treatment of Cytomegalovirus Infection

“…Notably, we also observed relatively lower unstable miRNA expression in the blood, which differs greatly from observations in lungs and livers. Several circulating HCMV miRNAs have been previously described as potential biomarkers, and were associated with hypertension, diabetes, and transplantation [25,45,46]. In those studies, miRNA expression was not detected in certain patient blood samples, consistent with our observations.…”

“…In those studies, miRNA expression was not detected in certain patient blood samples, consistent with our observations. Therefore, viral miRNA expression in the blood appears to change constantly and may be subject to multiple regulatory mechanisms [25]. …”

“…Therefore, although the miRNAs in Group 1 were strongly expressed during in vivo infection, they do not appear to play a large role in the regulation of viral replication. In a recent clinical study, miR-UL22A-5p—which is encoded by HCMV—was used as a biomarker during transplantation [25]. The authors demonstrated a significant regulatory role for miR-UL22A-5p in host gene expression by targeting the transcription factor C-MYC as well as many proteins involved in antigen presentation.…”

“…Recently, HCMV miR-UL22A-5p was identified as a potential biomarker for transplantation, suggesting that miRNAs encoded by HCMV are associated with specific virologic and clinical outcomes [25]. However, further investigation has been limited due to the rigorous species specificity of HCMV.…”

Distinct expression profile of HCMV encoded miRNAs in plasma from oral lichen planus patients

“…Notably, the majority of the 5 miRNAs identified in our study have been reported to be related to some HCMV infection diseases, for instance, hcmv-miR-UL22a-5p may be a potential predictor of clinical and virological endpoint in solid organ transplant patients [31], and increased hcmv-miR-UL112-3p was also reported to be related with glioblastoma, rheumatoid arthritis, diabetes mellitus essential hypertension as well as congenital infection [18, 19, 32]. All these results indicate that these HCMV encoded miRNAs may share similar physiological and pathological roles in HCMV infection related diseases as well as in OLP, eventhough much further study is needed to confirm this.…”