T

he Malayan flying lemur is a small brown animal with buggy eyes. It has extra skin stretching from its neck to its toes that it uses to glide between the treetops in Southeast Asia. In August of this year, a group of Czech scientists discovered another trait of this mammal: Deep within its genome is DNA of the oldest extinct virus related to HIV. They dated it to be around 60 million years old — meaning it was circulating when Europe and Greenland were still connected.

A lot of virus-fighting happens in the “now” — developing drugs, predicting where viruses will spread, and quarantining those infected.

But a relatively new field of research called paleovirology is taking a broader view: considering viruses on an evolutionary scale.

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In the case of the flying lemur, the extinct virus pushes back the origins of HIV’s family of viruses by tens of millions of years — and along with it, the viral iterations that scientists can study to learn how viral infection strategies originated, how they’ve changed, and how host immune defenses adapted in response.

At the heart of the research is the growing awareness that we’ve lived alongside viruses for millions of years — and that buried in the traces of those relationships could be insights into how we battle them in the future.

Paleovirologists take advantage of the fact that a common type of virus, the retrovirus, leaves a mark in its host after infection.

Retroviruses use reverse transcription to make copies of themselves. Their genome is made of RNA, which they convert to DNA, and insert into the genome of their host, like ripping a hole in a shirt, and sewing in a patch. After the virus has weaved in their own DNA, they use the host’s chromosomes as a template to make more viruses. When this happens in cells that will become sperm or eggs, the inserted viral DNA strand will be inherited by all of the host’s descendants, and become “endogenized.”

This is the fossil that paleovirologists are hunting for. These viral bits of DNA persist long after the virus itself has gone extinct. Its DNA sequence is all that’s left, a skeleton left buried deep in the layers of host’s genome. Finding fossils of different ages, then, can show their evolution throughout history.

Like the real fossil record, the viral record can be spotty. But it’s much richer than digging for fossils in the dirt. There is more retrovirus DNA in a human’s genome than there is DNA that encodes for protein. Each person has around 8 percent viral DNA, leftovers of millions of years of viruses infecting and integrating with our ancestors.

The long history of lentiviruses

In the 1980s, as the HIV/AIDS epidemic spread rapidly throughout the world, researchers estimated that its family of retroviruses, called lentiviruses, could only be a few thousand years old. In 1988, Nature published a study claiming that HIV-1 had evolved from its ancestor, HIV-2, as recently as 40 years prior.

Thanks to paleovirology, new evidence shows those estimates were very wrong.

In 2007, Aris Katzourakis, an evolutionary biologist at the University of Oxford, saw evidence of lentivirus DNA in the genome of the present-day European rabbit. At first, he thought his data was contaminated. Other retroviral DNA has been found in genomes for decades, but no one had yet seen a lentivirus. The common belief was that lentiviruses simply could not infect the germ line, or must be too young to have left a trace. But Katzourakis’s data was correct: In 2007, he and his collaborators published that they had found the first endogenous lentivirus.

By 2009, Katzourakis was able to date the lentivirus, called RELIK. He found RELIK DNA in the same location in a European rabbit and hare, meaning they infected around the same time, similar to finding fossils in the same rock layer in two different countries. Katzourakis also knew when the rabbit and hare split off from a common ancestor. If both the rabbit and hare carried the viral fossil, then Katzourakis could confidently say that RELIK had to be at least as old as their common ancestor: 12 million years.

“You’re digging into these genomes on your computer and suddenly finding these ancient relatives of viruses,” he said. “It’s like finding a miraculous fossil that a physical paleontologist could not hope to unearth. And with a few computer searches, you’re uncovering events like that.”

Since then, endogenous lentiviruses have been found in ferrets, lemurs, and the Malayan flying lemur (which is technically not a lemur, but a colugo). With each new lentivirus, paleovirologists are learning how old the lentivirus lineage really is.

Finding out that HIV has a relative that’s millions of years old, and not 2,000, opens all sorts of avenues for basic research. The modern HIV epidemic could have happened in some version before, possibly many times, in early mammals. The virus could have jumped species, infected new hosts, developed immunities, or been passed without pathogenic consequences.

For example, Katzourakis has found endogenous Ebola-like viruses in wallabies and opossums in Australia — though there are no known present-day descendants of Ebola there. That indicates that at some point in history, the ancestors of Ebola managed to move from mammals in Africa to mammals in Australia. Piecing together a similar transmission route for lentiviruses could help paleovirologists examine the moments when HIV-like viruses jumped species.

We know that happened at least once — from monkeys to humans — because both are still alive. But using paleo methods opens up the possibility of seeing such jumps tens or hundreds of times. And each of those could give telling information, said Welkin Johnson, a virologist at Boston College, because many of the most pathogenic viruses are the ones that recently jumped species.

“We need to think of the way lentiviruses interact with their hosts, and overcome their host’s defenses, on evolutionary timescales,” Katzourakis said. “Understanding these interactions will be important if we are to eradicate HIV.”

Drugs informed by evolution

Other drug targets could result from learning about the evolution of antiviral genes in a host. Humans have hundreds of antiviral genes that have evolved alongside viruses.

One such human antiviral gene is called APOBEC. HIV and other lentiviruses have a corresponding gene, called Vif, which is perfectly adapted to counter it. Paleovirology proved that Vif is the result of a long relationship with APOBEC, and now biologists, including those in Katzourakis’s lab, are actively looking for ways to disable it as a therapy for HIV.

Another antiviral gene, called TRIM5a, isn’t effective at stopping HIV infections in humans either, but can do so in the rhesus macaque. Harmit Malik, a evolutionary geneticist at the Fred Hutchinson Cancer Research Center in Seattle, has used the viral fossil record to show why.

A human’s TRIM5a gene was adapted to defeat a different virus, he says, that infected our ancestors 5 million to 7 million years ago. Malik and his colleague Michael Emerman resurrected the core protein of the extinct virus and showed that humans’ version of TRIM5a was well suited to counter it. If our TRIM5a was a piece of a puzzle, it fit with another virus; it’s the wrong shape to protect against HIV-1.

Taking that knowledge, Malik and Emerman were able to swap in a single amino acid residue from the rhesus macaque TRIM5a gene and produce a TRIM5a gene that, in the lab, could protect against HIV-1. This kind of application has a ways to go before it can applied to therapies for humans. But as more of the fossil record is uncovered, Malik is hopeful. “It has the benefit of potentially augmenting the antiviral profile of human genes,” he said.

Other paleovirologists study historical antiviral measures that did work, for clues as to why.

Paul Bieniasz, the head of the laboratory of retrovirology at Rockefeller University, studies extinct viruses to see what proteins they expressed, and how they fared against current antiviral genes. “In the case of the extinct viruses we see, it appears that the host’s defenses won the battle,” Bieniasz said. “What we’ve been trying to do ever since is to figure out how these extinct viruses became extinct, what extinguished them.”

The mutual agreement

Hanging on the wall in Welkin Johnson’s office at Boston College is a print of Darwin’s Galapagos finches. It’s a hallmark image for any evolutionary biologist — even Johnson, and other paleovirologists, whose organism of choice isn’t technically alive.

The field of paleovirology is often described in terms of war. Common metaphors describe a genome that is “scarred” from an “ancient battleground,” or a million-year-old “arms race” between virus and host. But it’s a strange sort of battle, because if the host loses the war, the virus goes with it.

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In fact, the viral fossil record can also reveal many instances of less antagonistic relationships between a virus and its host. One can find examples of exaptation, when a host begins to use viral DNA for its own benefit.
 In mice, a gene called Fv1, which originated as an endogenous retrovirus, now has antiviral properties. All mammals, including humans, have a gene called ENV that’s been co-opted from a viral gene and now plays a crucial role in placenta formation.

Johnson thinks that for all the ways paleovirology can help us understand and counteract diseases like HIV, there’s a bigger picture.

“We’re all having trouble letting go of the idea that the only reason to be interested in viruses is because you’re trying to cure something,” Johnson said. “Rather than to understand it’s just as much about understanding life as studying metabolism, mitochondria, trees, or photosynthesis. Every virus that’s alive today is a success story. Every organism that survives today is a success story. And they did it together.”

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