As the COVID-19 pandemic continues, the virus that causes the disease, SARS-CoV-2, is a frequent subject of popular science articles. Headlines about the origins and spread of the virus continue to dominate social media feeds.
But SARS-CoV-2 is not the only virus worth reading about. Another group of viruses—the retroviruses—have an even more interesting relationship with humans. They are a family of viruses that have effectively merged their genetic material with the genomes of their human hosts—a fossil record, if you will, of ancestral infection that stretches back through evolutionary time. They are frozen in time, like insects trapped in amber.
For the most part, these vestigial relics remain silent and are no longer capable of propagating infection. However, as one research team led by Dr. Daniel DeCarvalho in the Faculty of Medicine at the University of Toronto discovered, reawakening these fossilized virus remains may have some surprising benefits in the fight against another biological adversary: cancer.
The retrovirus life cycle
The word ‘virus’ comes from the Latin word for poison. Each virus is composed of a set of genetic instructions surrounded by a protective protein layer. Viruses enter host cells to hijack replication machinery in order to reproduce. In fact, viruses are unable to reproduce outside of a host; without a host, viruses exist essentially as static organic particles, neither growing nor respiring, leading some to question whether viruses can properly be considered lifeforms at all.
Information in a biological system tends to flow from DNA to RNA to proteins. For retroviruses, however, this paradigm is partially reversed. The RNA-based viral genome is converted to DNA, which then integrates into host genomes. Sometimes this viral integration occurs in cells that pass on genetic information to future generations, including sperm and egg cells. The viral information then becomes a part of the genomes of subsequent generations. In humans, around eight percent of our entire genetic map is made of human endogenous retroviruses (HERVs).
Given their pathogenic origins, HERVs are not expected to provide many benefits to us as hosts. The majority of HERV sequences have little effect on the body. However, there are some notable exceptions in which retroviral proteins and their regulatory elements have been co-opted and repurposed for cellular use. For example, HERV-derived proteins in the placenta play key roles in mediating cell fusion and suppressing maternal immunity to protect the fetus.
Fighting cancer with retroviruses
In 2015, the DeCarvalho lab revealed that reactivating ancient genomic retroelements in cancer cells causes them to behave as though they have been infected, a phenomenon dubbed ‘viral mimicry.’ The pseudo-infected cells then trigger a potent immune reaction that allows the body to fight the malignancy like an infection.
In a new study published this month in the journal Nature, DeCarvalho and collaborators reveal how some cancer cells have learned to fight back against viral mimicry and outwit the immune system.
More specifically, their research described how some cancer cells have learned to avoid viral mimicry-mediated destruction. An enzyme known as ADAR1 disrupts the viral mimicry mechanism. The result is protection from immune destruction and survival of the malignant cells. However, the research also reveals that deletion of ADAR1 in these cells restores their vulnerability to drugs that induce viral mimicry, thus allowing resistant cells to be targeted.
In an interview with the Faculty of Medicine, DeCarvalho said these results could create new cancer therapies in the future. “Since the ADAR1 activity is enzymatic, our work provides an exciting new target for drug development efforts for a completely new class of drugs that could exploit these ancient weapons in our genome,” he said.
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