Inherited Chromosomally Integrated Human Herpesvirus 6 Demonstrates Tissue-Specific RNA Expression In Vivo That Correlates with an Increased Antibody Immune Response

Human herpesviruses 6A and 6B (HHV-6A and HHV-6B) are human viruses capable of chromosomal integration. Approximately 1% of the human population carries one copy of HHV-6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo and how it shapes the immunological response are still unclear. In this study, we screened DNA sequencing (DNA-seq) and transcriptome sequencing (RNA-seq) data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6Aand 4 iciHHV-6B-positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B gene expression was found across multiple tissues, with the highest levels of gene expression in the brain (specifically for HHV-6A), testis, esophagus, and adrenal gland. U90 and U100 were the most highly expressed HHV-6 genes in both iciHHV-6Aand iciHHV-6Bpositive individuals. To assess whether tissue-specific gene expression from iciHHV6A/B influences the immune response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B subjects were identified. Plasma samples from iciHHV-6A/B and ageand sex-matched controls were analyzed for antibodies to control antigens (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and influenza virus [FLU]) or HHV-6A/B antigens. Our results indicate that iciHHV-6A/B subjects have significantly more antibodies against the U90 gene product (IE1) than do non-iciHHV-6-positive individuals. Antibody responses against EBV and FLU antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as U47, U57, and U72, were identical between controls and iciHHV-6A/B subjects. CMV-seropositive individuals with iciHHV-6A/B have more antibodies against CMV pp150 than do CMV-seropositive controls. These results argue that spontaneous gene expression from integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust HHV-6A/B-specific antibody response. IMPORTANCE HHV-6A and -6B are human herpesviruses that have the unique property of being able to integrate into the telomeric regions of human chromosomes. Approximately 1% of the world’s population carries integrated HHV-6A/B genome in every cell of their body. Whether viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a unique tissue-specific gene expression data set, we showed that the majority of tissues from iciHHV-6 individuals do not Citation Peddu V, Dubuc I, Gravel A, Xie H, Huang M-L, Tenenbaum D, Jerome KR, Tardif J-C, Dubé M-P, Flamand L, Greninger AL. 2020. Inherited chromosomally integrated human herpesvirus 6 demonstrates tissue-specific RNA expression in vivo that correlates with an increased antibody immune response. J Virol 94:e01418-19. https://doi.org/10.1128/JVI .01418-19. Editor Jae U. Jung, University of Southern California Copyright © 2019 Peddu et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to Louis Flamand, louis.flamand@crchudequebec.ulaval.ca, or Alexander L. Greninger, agrening@uw.edu. Received 21 August 2019 Accepted 30 September 2019 Accepted manuscript posted online 9 October 2019 Published PATHOGENESIS AND IMMUNITY