Wednesday, January 9, 2013
Although his goal is to someday help destroy HIV and other viruses and retroviruses that form persistent, lifelong infections, biologist Chris Sullivan can’t help but admire the strategies that many of these viruses have evolved to evade our defenses.“It’s brilliant,” says Sullivan, associate professor of molecular genetics and microbiology. “Take Herpes simplex virus 1, for instance, which is one of the masters. It goes in and infects very long-lived neurons, and then stays dormant, or latent, in that primary reservoir. It just hides out there, invisible to our adaptive immune system, waiting for the right time to attack.”
See video of Sullivan Fighting the Viral Wars, starring toy soldiers and Legos. Seriously.
When it does attack, HSV-1 hedges its bets. It sends out viral particles that only go lytic—start replicating rapidly, destroying cells—when they’re at the surface of our skin, far away from the primary reservoir. The reservoir, meanwhile, stays hidden.
This story was written by Daniel Oppenheimer in the College of Natural Sciences for the college’s website.
So even when we win the battle against the lytic cells, which manifest as cold sores, the war isn’t over. The latent virus remains in its hideout, running silent, waiting for the next opportunity to attack.
That’s where we stand now, in our wars against these viruses. It’s why in times of stress and illness the cold sores come back, for the roughly 60 percent of Americans infected by HSV-1. It’s why HIV can be managed but not eradicated. It’s why Kaposi’s sarcoma-associated herpes virus (KSHV), which is the virus that Sullivan has been studying most closely, can lay low for decades only to appear at the worst possible time, in the form of nasty tumors, when your immune system is compromised by AIDS or chemotherapy.
To win the war against these viruses in a more decisive fashion, something has to change. Our immune system has to be able to see and recognize these reservoirs of latent virus. Then all the squadrons of white blood cells that have become so good at fighting the viruses in their lytic form should be able to finish the job.
With the help of a $500,000 grant from the Burroughs Wellcome Fund, Sullivan is working to understand how latent viruses hide from our adaptive immune response, and whether there are any vulnerabilities that might be exploited to make them visible, so that we can kill them all.
“It’s the Holy Grail,” Sullivan says. “We call it ‘purging the latent reservoir.’”
To understand Sullivan’s strategy for finding the Grail, which revolves around small “suicide elements” in the viral genome, it helps to begin with the mechanism these viruses use to hide from our immune systems.
Our adaptive immune system has evolved to see and respond to viruses when they’re dangerous, which is when a lot of their genes are turned on and cranking out proteins.
In their latent state, however, most of their genes are turned off. The genes are still there, of course, but they’re hidden from the machinery in the host cell that makes proteins. The few proteins that are made only enable the virus to replicate and subsist. They don’t do any damage to the host cell, and so don’t trip any alarms.
When KSHV is lytic, for instance, more than 75 genes are turned on. These genes can generate thousands of virus particles in a single cell. During latency, by contrast, only three or four genes are turned on.
For a long time the virology community assumed that that was the end of the story. Very few genes turned on, very few proteins. Recently, however, scientists have discovered that the latency state isn’t quite so stable as was thought. A lot of the genes that are supposed to be turned off are “leaking.” Occasionally their blueprints become visible to the rest of the cell. If that leads to protein expression, as it typically would, that could mean trouble for the virus.
“It’s like a cliff,” says Sullivan. “You don’t sort of fall of a cliff. You either fall or you don’t. If you are a virus and you accidentally make proteins that haven’t evolved to be camouflaged, you alert the immune response, and you get cleared.”
The evidence of these leaks forced virologists to look again at the model. One possibility was that sufficiently few errant proteins were being made that the immune system remained clueless.
What Sullivan has begun to document is a considerably more elegant possibility. The viruses seem to have evolved a back-up plan. They have a way to take care of the leaks, and short circuit the process.
“We call them ‘suicide elements,’” he says.
Suicide elements, which Sullivan and his colleagues have found in KSHV, are small regions on viral mRNAs that are sensitive to whether the virus is in its lytic or latent state. If latent, then the suicide elements shut down the leaks, preventing the production of proteins.
If, however, the virus is lytic, these suicide elements actually flip their function. They help ramp up protein production, which makes the virus all the more nasty when it’s time for it to be nasty.
“We haven’t proven that these elements are necessary to keeping the virus hidden during latency,” says Sullivan. “But what we know for sure is that the viruses have them, and they are capable of cranking down expression. And the only thing that makes sense to me is that somehow this helps with latency, otherwise you are going to slow up your own replication cycle for no good reason.”
Sullivan believes that if he’s right about the purpose of these suicide elements, they could prove the key to a therapy that would purge the latent reservoir.
“What happens in my hypothetical world,” he says, “is you have a drug that disables the suicide elements. So now these protein leaks from the virus aren’t hidden from the immune response any more, and our own immune system can clear the infection.”
So far Sullivan has documented the suicide elements in KSHV and one retrovirus. He believes that they are likely to exist, at a minimum, in the seven other known strains of herpes, and very possibly in HIV. Which means that a treatment for KSHV, of the sort that Sullivan envisions, might be adaptable to those viruses as well. So no more cold sores, but also, more importantly, a true cure for HIV.
“That’s the dream,” he says.