Old virus, new host

How do retroviruses survive in a hostile new host environment? Mary Poss's research suggests a key role for the innate immune system.

Mary Poss's research subjects range from the very large—cougars native to the Northern Rockies—to microscopic viral genomes. By studying the molecular biology of viruses and their hosts on a variety of scales, Poss—a Penn State professor of biology and veterinary science—hopes to gain a greater understanding of how viruses evolve in response to changing environments.

Lentiviruses, a group consisting of several viruses, including HIV, that cause immunodeficiency diseases in humans and other mammals, are at the center of Poss's work. She is particularly interested in a feline strain of lentivirus found only in wild cougars. "We have a lot of information about this particular strain," said Poss. "It's a cousin of HIV, with similar molecular biology. And we know that the virus's life cycle in its feline hosts is very similar to that of primate immunodeficiency viruses: there are many wild felines that have this infection and don't get sick."

Lentiviruses belong to a family of viruses called retroviruses, which are defined by their ability to replicate by converting RNA into DNA. This backwards transcription is an error-prone process that can create high genetic diversity in each new generation of virus, making retroviruses popular tools for investigating molecular evolution.

"Our experiment," explains Poss, "was to infect domestic cats with the virus. Like the cougars, the cats don't get sick with the virus but they do become persistently infected. [I.e., the virus is weakened but not killed by the body's immune response.] The focus of our study is on why there was persistence."

When an antigen, such as a novel virus, enters the body, the immune system can respond in one of two ways. It can mount a non-specific, innate response that fights the immediate infection but doesn't confer any lasting immunity by the host; or it can adapt, learning to recognize specific pathogens and to remember those pathogens over time.

"When you get a tetanus shot," notes Poss, "you are getting a small bit of the tetanus toxin and you initiate an adaptive response. The first time you are exposed you don't have a memory of it...you have to learn. That's the adaptive immune system at work." The next time you are exposed, your immune system 'remembers' the attacker and generates a potent, rapid, and specific response to it.

Poss and her colleagues knew that the immune systems of their infected cats had never encountered a cougar virus before. Yet at first, "We couldn't find any evidence of a protective immune response from them," she says. "We looked for adaptive responses and there weren't any. But what we found is that the host mounted a very robust innate response, which is genetically encoded."

"We hadn't realized how important innate responses are to new virus infections," Poss adds. "In this case the immune system basically shot holes in the virus genome." This "shooting of holes" in turn triggered a vigorous reaction in the invading virus. As Poss explains it, the virus begins to rearrange its own genome—a process called recombination—in such a way as to come to a new equilibrium with the host. "The innate immune system in the cats basically disabled the virus," she says. "But despite this attack, we saw it persist in the host. The virus doesn't go extinct." Poss suspects this survival is related to changes in the virus's replicating enzyme, reverse transcriptase, which may regulate the recombination rate in response to changes in the host environment.

As Poss puts it, "Recombination is a strategy a virus uses to help itself recover from potentially fatal attacks on it. If you're under attack, genetic diversity is a good thing. Something might survive." In her data, she notes, "We saw enhanced recombination rates, which supports the idea that viral recombination increases in unfavorable environments. In turn, this increases the chances of the virus persisting in a new host species."

And what of the infected host? "Not all virus infections make you sick," reminds Poss. "Many people—and animals—don't have any clinical consequence of a viral infection. Lentiviruses are typically chronic, persistent infections, rather than acute ones. Disease can take years to develop."

There are good drugs available for HIV, she notes ("though not to most infected people in the world). Ironically, these seem to work by helping both the virus and the host survive. "Some of these therapies increase the virus's recombination rate, explains Poss. "Any time you increase predation on the virus and decrease its fitness and ability to reproduce, you also increase its genetic diversity and the probability that it will survive in a hostile environment."

Mary Poss, Ph.D. and D.V.M., is professor of biology and veterinary and biomedical sciences in the Eberly College of Science.

Last Updated May 21, 2007