Spontaneous gene expression in iciHHV-6A/B individuals leads to increased HHV-6 IE-1A/B and CMV antibody response; higher levels of RNA were found in iciHHV-6A brains

A comprehensive study of DNA and RNA-Seq data demonstrated in vivo gene expression in many iciHHV-6 tissues, with strong expression of U90 encoding the IE-1 protein and matching elevated antibody response in iciHHV-6 individuals compared to controls. More viral RNA was expressed in the brain tissue of iciHHV-6A brains than in those with iciHHV-6B.

Vikas Peddu in Alex Greninger’s lab at University of Washington looked at DNA and RNA-Seq in ciHHV-6 individuals mined using data from 650 records in the Genotype-Tissue Expression (GTEx) project. He found U90 (the IE-1A transactivator) and U100 (envelope glycoprotein) had the highest level of expression in both ciHHV-6A and ciHHV-6B individuals.

Alex Greninger and Vikas Peddu from the Greninger Lab, University of Washington Medicine, Clinical Virology

Alex Greninger and Vikas Peddu from the Greninger Lab, University of Washington Medicine, Clinical Virology

Theorizing that the increased antigen burden in ciHHV-6 individuals might also increase antibody levels to HHV-6, Greninger then teamed up with Louis Flamand at University Laval in Quebec City, who screened 15,498 heart disease patients from the Montreal Heart Institute biobank, to identify 85 ciHHV-6 patients.

About a third of iciHHV-6 individuals had 25X higher antibody titers to HHV-6 immediate early (IE-1A) compared to controls. Mean antibody responses to ciHHV-6 1E-1B were 13X higher in ciHHV-6 individuals than controls.

Individuals with iciHHV-6 had 5-fold higher CMV pp150  antibodies; that ratio was statistically significant for iciHHV-6A. Individuals with iciHHV-6A also had higher levels of TNF alpha than iciHHV-6B individuals or controls.

A previous study demonstrated that iciHHV-6 individuals could reactivate with their inherited strains, with pathological effect (Endo 2014). This new study sheds light on the biological consequences of low level gene transcription in iciHHV-6 individuals.

Louis Flamand, Annie Gravel and Isabelle Dubuc, CHU de Quebec, University Laval

Of interest, there was a high percentage of ciHHV-6A patients in the Montreal Heart institute cohort, at 54% of the 85 identified. Most studies, such as the previous prevalence study done in Canada (Gravel 2015) identified more iciHHV-6B than iciHHV-6A patients.

Read the full paper: Peddu 2019

Studies # Ici # Ici % iciHHV-6A iciHHV-6B
CARTaGENE 19,597 113 .58% 41% 59%
Montreal Heart Institute 15,498 85 .55% 54% 46%
Genotype-Tissue Expression project 650 6 .92% 33% 67%

Antibodies to HHV-6 IE1A (immediate early) antibodies were significantly elevated in iciHHV-6A/B individuals compared to antibodies against an HHV-6 glycoprotein U72