Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo

Abstract

Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are highly prevalent viruses unique in that they, besides Epstein-Barr virus, are the only human herpesviruses capable of chromosomal integration. When a chromosomal integration event happens in a germ cell the resulting progeny will have one copy of the virus in all of their cells, referred to as inherited chromosomally integrated human herpesvirus-6 (iciHHV-6). Active HHV-6 infections in those who are iciHHV-6 positive confound current DNA based PCR assays, highlighting a necessity for mRNA-based assays. As the transcriptional state of iciHHV-6 has not been defined in vivo, it is unclear which HHV-6 genes best determine actively infected iciHHV-6 individuals. Here, we screened DNA- Seq and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, the HHV-6 genes U90 and U100 were expressed in the brain, testis, breast, adrenal gland, lungs, salivary gland, esophagus, skeletal muscle, colon, tibial nerve and artery, adipose tissue, heart, skin, and thyroid. Additionally, high levels of HHV-6 gene expression were detected in the brain, testis, esophagus, and adrenal gland. We also analyzed data from the Synapse Mount Sinai Brain Bank and found similar brain tissue expression in the 4 iciHHV-6 positive samples. We found no expression of U38, a viral polymerase subunit found to be expressed in HHV-6 active infections, in GTEx whole blood RNAseq samples. However, using an RT-qPCR assay specific to the HHV-6A and -6B U38 genes, we saw that U38 was expressed in some iciHHV-6 positive PBMC samples submitted for iciHHV-6 testing.