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Faculty Focus

Charles Wira, Ph.D.: Viral warrior

By Amos Esty

Charles Wira's most recent scientific breakthrough came about as a result of thinking like a virus.

A professor of physiology at DMS, Chuck Wira studies how human immunodeficiency virus (HIV) infects cells in the female reproductive tract—a problem that has only recently started to attract significant attention. About 33 million people worldwide are currently infected with HIV, and 85 percent of new cases are the result of sexual transmission from men to women.

That means it's essential to know how the initial infection occurs, says Wira (whose name is pronounced WEER-uh). "If you don't understand the events taking place at the main portal of entry," he points out, "then you're not going to make very much progress in terms of coming up with protective mechanisms."

Earlier this year, Wira began developing a new answer to the question of how HIV evades the immune system and establishes itself in the female reproductive tract. His central insight is that sex hormones temporarily suppress several components of immunity just after ovulation. This process results in what Wira calls a "window of vulnerability," a seven- to ten-day phase in the middle of the menstrual cycle during which women might be more likely than at other times to contract HIV and other diseases.

Wira's findings, published this past fall in the journal AIDS, were the culmination of years of research and could lead to new lines of attack in the battle against HIV. Recent setbacks in HIV treatment—including the cancellation of a vaccine trial in 2007 and the failure of a microbicide trial that same year—make his recent finding all the more important.

Given his current interest in human disease, it's a bit surprising that as an undergraduate, Wira studied animal husbandry. "I thought I wanted to be a cattle rancher," he explains. But the

HIV exploits a "window of vulnerability" in the female reproductive tract, says Wira.

problem with ranching, he says, was that "you had to be a millionaire [and] buy into it, or marry into it, and neither of those was a good possibility." Instead, "after a series of bumpy transitions," he earned a master's degree in physiology from Michigan State University. Wira then moved east to enter the fledgling Ph.D. programin physiology at Dartmouth Medical School, where he became the first graduate student in the lab of physiology professor Allan Munck, Ph.D.

Munck was studying glucocorticoids, a type of hormone involved in metabolism, when Wira arrived. Wira was a "very dedicated" student, Munck recalls, but it was clear his primary interests lay in reproductive biology. Munck says that the time Wira spent in his lab was his "training ground, so to speak, so that he could go off on what he really wanted."

Wira had a chance to do just that in 1970, after earning his Ph.D., when he accepted a postdoctoral position at the University of Paris. There, he studied the effects of estrogen on the reproductive tract of female rats. Two years later he returned to DMS, this time as an assistant professor of physiology.

Over the next two decades, Wira continued to use rats as a model to learn more about the relationship between sex hormones and innate immunity. Among other findings, Wira discovered that the hormone estradiol—a formof estrogen involved in regulating ovulation—controls the presence of antibodies in the uterus. As the amount of estradiol increases, so, too, does the number of antibodies. As estradiol wanes, antibody levels decline.

Armed with the knowledge he'd gained from years of studying rats, Wira shifted his focus in the 1990s from rodents to humans. Beginning in 1993, a five-year Program Project grant from the National Institutes of Health allowed Wira to pull together a number of collaborators with expertise in different aspects of the immune system. For the rest of the decade, Wira continued to study immunity in the female reproductive tract. He also "became intrigued," he says, with the idea that his research might have implications for HIV infection. To help him pursue this line of research, Wira contacted DMS microbiologist Alexandra Howell, Ph.D., who by that time had been studying HIV for several years.

In 1997, Wira, Howell, and several other investigators made an important discovery. In a paper published in the Journal of Virology, they showed that HIV can infect cells throughout the reproductive tract—not just in the vagina and cervix, as had been previously thought. Since then, Wira has continued to work on defining the roles of the different components of immunity and on applying that understanding to HIV infection. And that brought him to his recent breakthrough.

Wira traces what he calls his "watershed moment" to a regular weekly lab meeting early in 2008. Munck, who is now an emeritus professor of physiology, challenged Wira to change his approach to solving the problem of HIV infection. "It just went through my mind," Munck recalls, "that it was really time to break

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Amos Esty is senior writer for Dartmouth Medicine magazine.

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