First ancient human herpesvirus genomes document their deep history with humans

(Press-News.org) For the first time, scientists have reconstructed ancient genomes of Human betaherpesvirus 6A and 6B (HHV-6A/B) from archaeological human remains more than two millennia old. The study, led by the University of Vienna and University of Tartu (Estonia) and published in Science Advances, confirms that these viruses have been evolving with and within humans since at least the Iron Age. The findings trace the long history of HHV-6 integration into human chromosomes and suggest that HHV-6A lost this ability early on.

HHV-6B infects about 90 percent of children by the age of two and is best known as the cause of roseola infantum – or "sixth disease" – the leading cause of febrile seizures in young children. Together with its close relative HHV-6A, it belongs to a group of widespread human herpesviruses that typically establish lifelong, latent infections after an initial mild illness in early childhood. What makes them exceptional is their ability to integrate into human chromosomes – a feature that allows the virus to remain dormant and, in rare cases, to be inherited as part of the host's own genome. Such inherited viral copies occur in roughly one percent of people today. While earlier studies had hypothesized that these integrations were ancient, the new data from this study provide the first direct genomic proof.

Recovering viral DNA from the distant past

An international research team led by the University of Vienna and the University of Tartu (Estonia) – in collaboration with the University of Cambridge and University College London – screened nearly 4,000 human skeletal samples from archaeological sites across Europe. Eleven ancient viral genomes were identified and reconstructed – the oldest from a young girl of the Iron Age Italy (1100–600 BCE). The remaining individuals covered a wide geographic and temporal range: Both types of HHV were found in medieval England, Belgium and Estonia, while HHV-6B also appeared in samples from Italy and early historic Russia. Several of the English individuals carried inherited forms of HHV-6B, making them the earliest known carriers of chromosomally integrated human herpesviruses. The Belgian site of Sint-Truiden yielded the largest number of cases, with both viral species circulating within the same population. 

"While HHV-6 infects almost 90% of the human population at some point in their life, only around 1% carry the virus, which was inherited from your parents, in all cells of their body. These 1% of cases are what we are most likely to identify using ancient DNA, making the search for viral sequences quite difficult", said the lead researcher of the study, Meriam Guellil, University of Vienna, Department of Evolutionary Anthropology. "Based on our data, the viruses' evolution can now be traced over more than 2,500 years across Europe, using genomes from the 8th-6th century BCE until today."

Ancient integrations, lasting consequences

The recovered genomes allowed the researchers to determine where in the chromosomes the viruses had integrated. Comparisons with modern data revealed that some integrations happened a very long time ago and passed down through generations for millennia. One of the two viral species (HHV-6A) appears to have lost its ability to integrate into human DNA over time – evidence that these viruses have evolved differently while coexisting with their human hosts. 

"Carrying a copy of HHV6B in your genome has been linked to angina–heart-disease", says Charlotte Houldcroft (Department of Genetics, University of Cambridge). "We know that these inherited forms of HHV6A and B are more common in the UK today compared to the rest of Europe, and this is the first evidence of ancient carriers from Britain."

A new chapter in virus–host evolution

The discovery of these ancient HHV-6 genomes provides the first time-stamped evidence for the long-term co-evolution of this virus with humans at the genomic level. It also shows how ancient DNA can reveal the long-term evolution of infectious diseases – from short-lived childhood infections to viral sequences that became part of the human genome. Discovered only in the 1980s, HHV-6A and HHV-6B can now be traced back to the Iron Age, offering direct genomic evidence for an ancient, shared history between viruses and humans. "Modern genetic data suggested that HHV-6 may have been evolving with humans since our migration out of Africa," says Guellil. "These ancient genomes now provide first concrete proof of their presence in the deep human past."

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