Complete Genome Sequence of Germline Chromosomally Integrated Human Herpesvirus 6A and Analyses Integration Sites Define a New Human Endogenous Virus with Potential to Reactivate as an Emerging Infection

Tweedy, Joshua; Spyrou, Maria A.; Pearson, Max; Laßner, Dirk; Kühl, Uwe; Gompels, Ursula A.

doi:10.3390/v8010019

Cited by 45 publications

(65 citation statements)

References 79 publications

(136 reference statements)

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“…Comparisons with the ciHHV-6A LEI-1501 genome (18) as a reference, also showed greater similarity among the ciHHV-6A genomes although the substitution frequencies are higher than among European ciHHV-6B genomes, indicating greater diversity among the ciHHV-6A genomes sequenced here (38). Notably the ciHHV-6A in the Japanese individual (HAPMAP NA18999) shows greater divergence from the other ciHHV-6A samples of European origin.…”

Section: Selection Of Cihhv-6 Carriers and Sequence Analysis Of Viralmentioning

confidence: 58%

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Zhang

Bell

Wilkie

et al. 2017

Preprint

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Human herpesviruses 6A and 6B (HHV6-A and HHV-6B; species Human herpesvirus 6Aand Human herpesvirus 6B) have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern non-integrated HHV-6 strains for which complete sequences are currently available. In addition ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 ±10,600 years ago. Despite the antiquity of some, and possibly most, germline HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation. IMPORTANCEInheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immune-compromised patients, in particular in organ transplantation and in stem cell therapy.

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Section: Selection Of Cihhv-6 Carriers and Sequence Analysis Of Viralmentioning

confidence: 58%

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Zhang

Bell

Wilkie

et al. 2017

Preprint

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“…30,157 Serological studies indicate that HHV-6 infects most children by age 2 years and that older siblings serve as a source of transmission. 29 HHV-6 has a number of forms-HHV-6, HHV-6B, and also CiHHV-6, which is chromosomally integrated 158,159 and can be reactivated.…”

Section: Epsteinàbarr Virus (Ebv; Hhv-4)mentioning

confidence: 99%

Viral Diseases Transmissible by Kissing

Limeres

Dios

Scully

2017

Saliva Protection and Transmissible Diseases

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“…As with all herpesviruses, HHV-6A/B establish lifelong latency, though it is unique in that it is the only human herpesviruses capable of chromosomal integration. The method of integration is thought to be the result of homologous recombination between the direct repeat (DR) regions on the right end of the HHV-6 genome and the subtelomeric regions of the human genome (3). In approximately 0.5-2% of the general population, integrated virus can be vertically passed through the germline, resulting in one copy of the HHV-6A/B genome in every cell in the resulting child’s body.…”

Section: Introductionmentioning

confidence: 99%

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expressionin vivothat correlates with increased antibody immune response

Peddu

Dubuc

Gravel

et al. 2019

Preprint

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35 Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are human viruses capable of 36 chromosomal integration. Approximately 1% of the human population carry one copy of HHV-37 6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated 38 human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo 39 and how it shapes the immunological response is still unclear. Here, we screened DNA-Seq 40 and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression 41 (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When 42 corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B 43 gene expression was found across multiple tissues, with the highest levels of gene expression 44 in the brain (specifically for iciHHV-6A), testis, esophagus, and adrenal gland. U90 and U100 45 were the most highly expressed HHV-6 genes in both iciHHV-6A and iciHHV-6B individuals. To 46 assess whether tissue-specific gene expression from iciHHV-6A/B influences the immune 47 response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B + subjects were 48 identified. Plasma samples from iciHHV-6A/B + and age and sex matched controls were 49 analyzed for antibodies to control antigens (CMV, EBV, FLU) or HHV-6A/B antigens. Our results 50 indicate that iciHHV-6A/B + subjects have significantly more antibodies against the U90 gene 51 product (IE1) relative to non-iciHHV-6 individuals. Antibody responses against EBV and FLU 52 antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as 53 U47, U57 or U72, were identical between controls and iciHHV-6A/B+ subjects. CMV 54 seropositive individuals with iciHHV-6A/B + have more antibodies against CMV pp150, relative to 55 CMV seropositive controls. These results argue that spontaneous gene expression from 56 integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust 57 HHV-6A/B specific antibody response.58 59 Importance 60 3 HHV-6A/B are human herpesviruses that have the unique property of being able to 61 integrate into the subtelomeric regions of human chromosomes. Approximately 1% of the 62 world's population carries integrated HHV-6A/B genome in every cell of their body. Whether 63 viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a 64 unique tissue-specific gene expression dataset, we show the majority of tissues from iciHHV-6 65 individuals do not show HHV-6 gene expression. Brain and testes showed the highest tissue-66 specific expression of HHV-6 genes in two separate datasets. Two HHV-6 genes, U90 67 (immediate early 1 protein) and U100 (glycoproteins Q1 and Q2), were found to be selectively 68 and consistently expressed across several human tissues. Expression of U90 translates into an 69 increase in antigen-specific antibody response in iciHHV-6A/B + subjects relative to controls. 70Future studies will be needed to determine...

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Complete Genome Sequence of Germline Chromosomally Integrated Human Herpesvirus 6A and Analyses Integration Sites Define a New Human Endogenous Virus with Potential to Reactivate as an Emerging Infection

Cited by 45 publications

References 79 publications

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Viral Diseases Transmissible by Kissing

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expressionin vivothat correlates with increased antibody immune response

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