Viruses and humans battle in a never-ending game of cat-and-mouse. The winners survive, and the losers die. Though viruses are fleet on their feet when it comes to evolution, humans aren't powerless. One trick we use comes from antiviral genes, which orchestrate immune defenses against invading viruses. They tether viruses to the cell's surface or mutate viral DNA. There's one problem: These defenses adapted to viruses that existed millions of years ago. Today, our antiviral genes can't adapt quickly enough to emerging pathogens.
Michael Emerman, a virologist at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, hopes to gain a deeper understanding of our current defenses against modern viruses by looking at the "fossil record" of past viruses. He digs through gene sequences in humans and other primates to find out when pathogens first emerged, and then compares how our antiviral genes adapted.
For instance, human immunodeficiency viruses (HIV) arose from simian immunodeficiency viruses (SIV) in chimpanzees, but HIV emerged in humans only within the past 100 years. Despite the similar origins, chimps aren't susceptible to this virus like humans are. The reason has less to do with SIV or HIV than with viruses that existed millions of years ago.
Emerman addressed these themes in a talk at the 2010 meeting of the American Association for the Advancement of Science in San Diego this February. Afterward, SciCom's Janelle Weaver probed for more.
What is a paleovirus?
A paleovirus is an ancient and extinct virus. Ancient viruses exerted evolutionary pressure on the human immune system to adapt, and this has consequences on our susceptibility to modern viruses. Last year, we had H1N1; ten years ago, SARS entered the population; 100 years ago, HIV entered the human population; 1,000 years ago it was the dengue virus; 10,000 years ago it was measles; and 50,000 years ago it was smallpox. Those are actually kind of recent in terms of evolutionary history. We believe there has been a series of much more ancient viruses that have driven the evolution of the immune system, specifically, antiviral genes.
How do viruses combat the activity of antiviral genes?
The viruses themselves evolve ways of getting around antiviral genes. HIV and SIV have proteins, such as Vif, which fight antiviral genes. The way Vif works is that it ties antiviral genes to the recycling machinery in the cell and destroys them. Because viruses and antiviral genes are working against each other, you can imagine how evolution takes place.
How do viruses and antiviral genes evolve?
Two things happen in their evolution. The host's antiviral genes need to recognize the virus, and the virus tries to evade the antiviral genes. This leads to evolutionary pressure for the virus to change, which leads to pressure for the host to change. This happens over and over again, and the rapid evolution is called positive selection.
This is not co-evolution; they're not evolving toward each other or in concert with each other. One thing is evolving, and it's winning. The other thing is going extinct. We are the descendants of the survivors.
"We evolved antiviral genes that acted against prior pathogens. Whether or not they work against our current pathogens is just a matter of luck. We were unlucky with HIV."
How quickly does selection take place?
Viruses can evolve very fast. HIV has adapted to humans in the last 100 years. Hosts evolve much more slowly than viruses. There are people who see evidence for the evolution of antiviral genes in the 10,000-year range.
How do you detect paleoviruses?
We can detect them by directly seeing their fossils in the genome, or we can infer indirectly the existence of paleoviruses by the signatures of their selection on ancient antiviral genes.
The first way—seeing paleoviruses directly—is easier. We can see endogenous retroviruses, a type of virus that enters the nucleus and integrates into the chromosome. Once they integrate, they never come out again. That borrowed DNA will exist for as long as that cell exists. It can become part of the genetic legacy of the species. That sounds like a farfetched thing, but it has happened over and over again.
We can gauge when that happened by sequencing genomes from different primates. In each case where there is evidence of an endogenous retrovirus, there must have been an external paleovirus in the population at that time that gave rise to an infection of the germ line.
How prevalent is the evidence for paleoviruses in the genome?
There are 100,000 retroviral integrations in the human genome, from 31 different families of retroviruses. The amount of the genome that encodes for proteins is about 2%. The amount of the genome that is made up of vestiges of old infections is about 8%. This is actually a vast underestimate of the number of infections that occurred in human ancestors.
What does it mean when you see rampant evidence for paleoviruses in the genome?
It means the genome is filled with success stories. Each retroviral integration represents an extinct virus; none of them are now actively replicating. Each one is a success story where there was a retrovirus in the population that led to an infection in the germ line. That virus was removed from the environment because there was some evolutionary pressure. We are the descendants of the success stories.
How do you tell if a paleovirus was pathogenic?
These endogenous viruses only tell us about retroviruses. They don't tell us anything about any other type of viruses that infected human ancestors, and they don't tell us anything at all about whether they were pathogenic. We can learn about things that were not retroviruses and things that were pathogenic by looking at the effect of a paleovirus on the evolution of the antiviral genes. The signature of when there's pathogenic pressure is when the gene changed.
We have sequences of antiviral genes from many different species of primates. We use the sequences to reconstruct what genes would have looked like at different periods in evolutionary history. When we see a big change in genes, we predict there was a paleovirus.
Do humans and other primates share the same paleoviruses?
There are endogenous retroviruses that are shared among all primates, and there are some found only in hominids, hominoids, or humans. There are retroviruses in chimps and gorillas that are not in humans. Each species has its own history.
Do humans and other primates share the same antiviral genes?
Most of them we all have, but they don't all work. When we test these from a range of primates, we always find that some work better than others. Each primate has its own constellation because each primate has its own history of previous infections.
What does your research tell us about our defenses against modern viruses, like HIV?
We're interested in what role host genes play in the recognition of modern viruses. In modern times, HIV was transmitted four times from the chimp SIV to humans. At least one of those transmissions led to a pandemic: the strain infected 40 million people.
Nothing we have is supposed to be against HIV. HIV evolved only in the last 100 years. That's one of the reasons we're so susceptible. We haven't evolved anything against the virus. We evolved antiviral genes that acted against prior pathogens. And whether or not they work against our current pathogens is just a matter of luck. We were unlucky with this one.
The idea is that the antiviral genes we have are the consequence of our previous infections. Our current pandemics are a consequence of the constellations of our antiviral genes, which are due to selections by previous infections of our ancestors.
Why are chimps, but not humans, protected against HIV?
Humans are extraordinarily susceptible to HIV. Part of what we do is to figure out the constellations of antiviral genes that don't work against HIV in humans that do work in other primates. Some of the ways that HIV has adapted to humans has to do with particular changes in antiviral genes. One antiviral gene, called tetherin, prevents the virus from escaping from cells. It has the nice name because it tethers viruses to the cell's surface and prevents them from getting away. Tetherin works well in chimpanzees. But previous pathogenic pressure in human history selected for a change in human tetherin, and this change made tetherin less effective at combating HIV.
What's been the most surprising or important discovery your lab has made so far?
That's like making me pick my favorite child. I can't do that.
Maybe you could pick three.
The most surprising [Emerman muses]. I always pick the newest ones; I can't do that. We have a lot of interesting stuff.
Wanna pick one?
No.
Why do you think your research is important?
This concept that our antiviral genes are driven by ancient infections is relatively new. We're breaking ground in our understanding of how genes have evolved and what classes of viruses caused those changes. We still have a long way to go to understand how genes work together to limit viral infections.
Can you predict how well humans will defend themselves against emerging pathogens?
We can determine what antiviral genes humans have, and we can test them against different viruses and see whether humans make a response against the viruses. It's really a case-by-case basis. Until you know what the virus is, you can't predict what antiviral genes would be used to combat it.
Can you make any predictions for the H1N1 virus?
No, because you don't know how it's going to evolve. Evolution can't tell the future.
Janelle Weaver, a graduate student in the Science Communication Program at UC Santa Cruz, earned her bachelor's degree from Dartmouth College and her Ph.D. from Stanford University, both in psychology and neuroscience. She has worked as a science writing intern at the Stanford University News Service and the Santa Cruz Sentinel. This summer, she will work as a science writing and multimedia intern at the National Institute for General Medical Sciences in Bethesda, Maryland.
© 2010 Janelle Weaver
