by Remnants of ancient viral pandemics in the form of viral DNA sequences embedded in our genomes are still active in healthy people, according to new research recently published by my colleagues and I.
HERVs, or human endogenous retroviruses, account for about 8% of the human genome, left behind by infections suffered by humanity’s primate ancestors millions of years ago. They became part of the human genome because of how they replicate.
Like modern HIV, these ancient retroviruses had to insert their genetic material into their host’s genome in order to replicate. This type of viral genetic material is not usually passed from generation to generation. But some ancient retroviruses acquired the ability to infect a gamete, such as an egg or sperm, which passes its DNA to future generations. By targeting germs, these retroviruses were incorporated into ancestral human genomes over millions of years and may have implications for how researchers screen and test for disease today.
Active viral genes in the human genome
Viruses insert their genomes into their host in the form of a provirus. There are approximately 30 different types of endogenous human retroviruses in humans today, representing more than 60,000 proviruses in the human genome. They represent the long history of the many pandemics that humanity has been subjected to during evolution. The scientists think that these viruses were once widely infected in the population, since they have become not only in the human genome but also in the genomes of chimpanzees, gorillas and other primates.
Research from our laboratory and others has shown that HERV genes are active in diseased tissues, such as tumors, as well as during human embryonic development. But much was still unknown about how active HERV genes are in healthy tissue.
To answer this question, our laboratory decided to focus on one group of HERVs called HML-2. This group is the most recent of the HERVs, having gone extinct less than 5 million years ago. Even now, some of its proviruses within the human genome still have the ability to make viral proteins.
We examined the genetic material in a database of more than 14,000 tissue samples donated from all over the body. We looked for sequences matching all HML-2 proviruses in the genome and found 37 different HML-2 proviruses that were still active. There was some evidence of activity of one or more of these proviruses in the 54 tissue samples we analyzed. In addition, all tissue samples contained genetic material from at least one provirus that could still produce viral proteins.
The role of HERVs in human health and disease
Thousands of pieces of ancient viruses still in the human genome and that they can even create protein are attracting great attention from researchers, especially since related viruses that are still active today can cause breast cancer and AIDS diseases in animals.
Whether genetic remnants of endogenous human retroviruses can cause disease in humans is still being studied. Researchers have seen virus-like particles from HML-2 in cancer cells, and the presence of HERV genetic material in diseased tissues has been associated with conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis, as well as multiple sclerosis and even schizophrenia.
Our study adds a new angle to these data by showing that HERV genes are present even in healthy tissue. This means that the presence of HERV RNA is not enough to link the virus to disease.
Importantly, it also means that HERV genes or proteins may no longer be good drug targets. HERVs have been explored as a target for several potential drugs, including antiviral medications, antibodies for breast cancer and T-cell therapies for melanoma. Treatments that use HERV genes as a cancer biomarker must also take into account their activity in healthy tissue.
On the other hand, our research also suggests that HERVs may even be beneficial to humans. The best known HERV embedded in human and animal genomes is sycytin, a gene derived from an ancient retrovirus that plays an important role in the formation of the placenta. Pregnancy in all mammals depends on the virus-derived protein encoded in this gene.
Similarly, mice, cats and sheep have found a way to use endogenous retroviruses to protect themselves from the original ancient virus that created them. Although these embedded viral genes are unable to use their host’s machinery to create a complete virus, many of their damaged pieces spread throughout the body to disrupt the replication cycle of their progenitor virus if encountered by the host. Scientists theorize that HERV alone may have played this protective role in humans millions of years ago. Our study highlights a few other HERVs that the human body may claim or co-opt much later for this same purpose.
Remains unknown
Our research reveals a previously unknown level of HERV activity in the human body, raising as many questions as it answers.
Much remains to be learned about the ancient viruses that remain in the human genome, including whether their presence is beneficial and what mechanism drives their activity. It will also be important to see if any of these genes make proteins.
Answering these questions may reveal previously unknown functions for these ancient viral genes and help researchers better understand how the human body has responded to evolution alongside vestiges of these ancient pandemics.
This article is republished from The Conversation, a non-profit, independent news organization that brings you reliable facts and analysis to help you make sense of our complex world. Written by: Aidan Burn, Tufts University
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Aidan Burn receives funding from the National Cancer Institute.
