Winnipeg—Dr. Allan Ronald remembers the fateful call that came on Canada Day, 1975.

The Winnipeg General Hospital needed the infectious diseases specialist to look at an unusual mass on a man's groin, which doctors thought might indicate a strangulated hernia. The patient was in great pain, Ronald recalls, and he also had an ulcer on the inside of his foreskin. A cluster of similar cases came to the attention of doctors in Winnipeg soon after.

Ronald consulted other experts, but he suspected it was chancroid, a sexually transmitted disease rarely seen outside of Africa and Asia.

Tests showed he was right. In retrospect, doctors believe a prostitute may have caught it from a visitor from India or Africa and infected a string of others.

That phone call changed the course of Ronald's life and those of the infectious disease professor's students, setting off a chain reaction of scientific discoveries that contributed to the world's understanding of the human immunodeficiency virus, or HIV, which causes AIDS.

The Winnipeg connection to the AIDS story began in the late 1970s, when a World Health Organization official told Ronald he should contact a University of Nairobi professor named Dr. Herbert Nsanze, who had been studying chancroid in prostitutes there. The research partnership forged by those two men nearly 30 years ago, on the cusp of the worldwide AIDS epidemic, continues to this day.

The work in Kenya led to some profound discoveries: Breastfeeding can spread HIV from mother to child; STDs like chancroid and gonorrhea accelerate HIV transmission; and circumcision can protect men from contracting HIV.

But it was one of Ronald's star students and collaborators, Dr. Frank Plummer, who discovered that a small percentage of Nairobi prostitutes had a natural resistance to HIV and that the immunity runs in families. If Plummer can unlock the biologic secret to this immunity — the so-called Holy Grail of AIDS research — many people believe it could be harnessed to provide a vaccine against AIDS.

A testament to its importance, Plummer's Winnipeg team was recently awarded an $8.3 million (U.S.) grant from the Grand Challenges in Global Health initiative, launched by the Bill and Melinda Gates Foundation. The money will be used to study the genetic blueprint of 100 Nairobi-area sex-trade workers who are HIV-negative to try to determine why their immune-system response to the virus is so different.

The researchers are already making headway. At the International AIDS Conference in Toronto, which begins tomorrow, they'll discuss findings of a unique protein that is over-expressed in the genital tracts of HIV-resistant women, a protein that appears to inhibit the virus.

"It could possibly be used as a microbicide (vaginal gel applied before intercourse)," Plummer says. "That would be another dimension to this work."

The team's discoveries so far have helped to provide the scientific building blocks for nearly 25 vaccines now in development, says Dr. Wayne Koff, vice-president of research and development at the International AIDS Vaccine Initiative in New York. That includes a promising Merck & Co. vaccine currently in human trials.

"That initial set of observations led to a whole generation of vaccine development," Koff says.

When he made his first trip to Africa in 1980, Ronald took with him his colleague, Dr. Margaret Fast, a pediatric infectious disease specialist. The doctors set up shop in a corner office in Nsanze's laboratory and got down to work studying chancroid.

The next year, Ronald persuaded Plummer, then a medical fellow at the University of Manitoba, to come on board. After talking to Plummer's wife Carla, the young couple decided to go for a year.

"I went for a lark. I hadn't really done much travelling," Plummer recalls in a recent interview at his office at Canada's National Microbiology Laboratory in Winnipeg, where he is the scientific director. "It was a watershed year."

Plummer and Nairobi doctor Elizabeth Ngugi began organizing the prostitutes with chancroid they were seeing into groups for study. Ronald also invited a young Belgian doctor, Peter Piot, to join them. Piot, a co-discoverer of the Ebola virus, now has the world's top AIDS job as executive director of the Joint United Nations Program on HIV/AIDS.

Plummer worked in a busy STD clinic that was more like a factory. He was one of two doctors who saw nearly 600 patients a day with "every conceivable STD and, in some, three or four at once." He concluded that the best way to help these patients was in the lab, not in the clinic.

"You are never going to solve these problems by treating them," Plummer says. "You have to figure out how to prevent them."

After Nairobi, Plummer went to Atlanta's Centers for Disease Control and Prevention for more training. When he finished, Ronald recruited him to the University of Manitoba, gave him a faculty job, then made him head of the Nairobi project. He returned to Africa with his wife and growing family in 1984.

At this time, AIDS had begun its deadly march across the African continent. Plummer's group noticed some of the prostitutes didn't catch HIV and so they began to investigate.

For the next 17 years, the Manitoba team made a series of discoveries as they listened to the lessons the virus taught them.

"Frank has an incredible mind," says Ronald, who will receive the Gairdner Foundation's Wightman Award for leadership in medical science at a ceremony this fall. "We used to spend one or two hours every Sunday on the phone, working things out."

Ronald remembers when Plummer called him from Africa in 1986 to tell him how the birth control pill made sex workers more susceptible to HIV.

The same year, Plummer called to say uncircumcised men were at higher risk of catching HIV. Today, there are two large-scale trials in Africa examining the role of circumcision in HIV prevention, and the issue promises to be an important talking point at the AIDS conference. Plummer will be honoured on Tuesday evening by the drug firm Sanofi-Pasteur for his lifelong contribution to the fight against AIDS.

But Plummer's greatest contribution to HIV research will no doubt spring from the secrets found in the immune systems of the group of Kenyan prostitutes naturally immune to HIV.

These are women who have multiple sexual partners daily, don't always use a condom and still don't get infected. But if the prostitutes take a break from work to go out of the city for an extended holiday, for example, immunity seems to wane. Once they return to work, some have become infected. It's as if the constant HIV bombardment is needed to protect them, Plummer says.

Manitoba microbiologist Dr. Keith Fowke arrived in Nairobi in the 1980s as a graduate student to work with Plummer. Together, they discovered the prostitutes had signs of exposure to HIV — the virus was in the cells — but there was no infection.

"They don't use condoms all the time. Exposure rate is huge. So, despite that they aren't getting infected," Fowke says in an interview at his lab. "We believe their immune system is protecting them."

The University of Manitoba eventually hired Fowke, who now runs the immunity segment of the Gates study from his lab in the dark, concrete labyrinth that is the university's Basic Medical Sciences building. The office is a stark contrast to Plummer's digs a mere five-minute walk down the road at the six-storey, $175 million state-of-the-art National Microbiology Lab that houses Canada's only stock of lethal agents such as the Ebola virus.

Plummer's reputation and that of his team's was one of the reasons the federal government decided to build the country's only level-4 containment lab in Winnipeg, home to a high-security, special-operations centre that monitors global emerging diseases.

 

`Right now, one of the big challenges is we don't know which part of the immune system to stimulate'

 

Dr. Keith Fowke, microbiologisit

 

"Right now, one of the big challenges is we don't know which part of the immune system to stimulate," Fowke says. His group is looking at the role of killer T-cells that go after infections in the body. This is known as a cell-mediated immune system response.

The group also discovered that many of the prostitutes who were resistant to HIV were related: They were aunts, sisters, daughters of one another, Fowke says. And if a sex-trade worker is related to an HIV-resistant woman, they are many times more likely to be resistant to HIV infection than if they were related to an HIV infected person, he explains.

The team believes there could be one or more genes responsible for HIV-resistance, but the trick is to track them down and figure out what role they play in the immune system.

"Whether it's two recessive genes required, or a single dominant gene, we don't understand that yet and it's part of what our Gates project is trying to determine," Fowke says.

In his office at the microbiology lab, where security is so high every piece of mail is examined with an X-ray machine, in the loading docks, Plummer paused a minute before answering a question about the state of his life's work.

"It's like doing a jigsaw puzzle. You don't know what the final picture will look like but you see pieces. We are gradually getting clearer and clearer ideas. We know more and more of the genes that are related. But we don't really know what the whole picture looks like."

The Kenyan project has deep roots, and the link to Winnipeg is strengthened every passing year. Now, the University of Manitoba trains students like Julius Oyugi, who worked with Plummer's group as a technician for nine years before he got his Master's degree at Oxford University in England, which also has a contingent studying the Nairobi prostitutes. The Canadian government and the University of Manitoba are picking up the tab for Oyugi's PhD.

For the past 2  1/2 years, Oyugi and his family have called Winnipeg home.

He likes it, even if the winters are too cold and the summers bring pesky mosquitoes, but he wants to return to the University of Nairobi soon to continue his HIV research.

"It's always been my dream to become a scientist mainly in the HIV/AIDS area because of the fact it kills so many in Africa and we aren't doing enough to change," he says. "I'm hoping for a job back home."

Although scientists who converged on Nairobi to study the HIV-resistant prostitutes have been criticized for doing nothing to help the women escape grinding poverty and the sex trade, the women all receive free medical care, access to condoms and access to HIV/AIDS drugs. Not all the women were HIV-negative because some control groups of HIV-positive women were needed.

"They get good medical care," Fowke says.

"These are women from slum areas, they don't have a lot of possibilities and the Kenyan medical system is all private.

"If they want out of the sex trade, they can be referred to programs that'll teach them to find alternative ways of making a living, or even give them small business loans.

The women may be poor, but they want to contribute to fighting a disease that has killed so many of their colleagues. "Many of the women have said that if studying their blood they can fight AIDS, then they are happy to do that," Fowke says.

The U of M is sponsoring eight Kenyan scientists to join Plummer and Fowke at the AIDS conference.

When the meeting wraps up in Toronto next week, there's only one place the Kenyan contingent is keen to get to: They're heading west to visit Winnipeg, of course.