Twenty-five years is a long time in science.
In the world of HIV research, 25 years have transformed our understanding of the virus. We now have antiretroviral drugs that stop HIV from developing into AIDS and, when used prophylactically, can prevent infection. Scientists have tested an experimental HIV vaccine that shows partial efficacy and are hoping to improve this effect.
Twenty-five years is a particularly impressive time period when studying people. It can be difficult enough to maintain participants’ interest in studies lasting mere months, let alone years, and maintaining grant funding over decades takes perseverance. This month, Fred Hutchinson Cancer Research Center virologist Dr. Julie Overbaugh and her collaborators in Kenya and the U.S. celebrated the 25th anniversary of a unique group of HIV research participants — high-risk women in Mombasa, Kenya — who helped change the landscape of HIV transmission research. The first participants enrolled in February 1993.
“The Mombasa cohort has been the setting for some of the seminal studies on markers of HIV infection risk in high-risk women,” said Overbaugh. “It continues even now to shed light on factors that drive risk. These studies, in turn, provide opportunities to design ways to prevent new HIV infections, which is the ultimate goal of this work.”
In Kenya, HIV is primarily transmitted through heterosexual contact, and women are at higher risk than men. This is reflected in the makeup of the Mombasa Cohort — women at high risk of contracting HIV from male sexual partners — because the researchers wanted to address issues most relevant to the community, said Dr. Jared Baeten, vice chair of Global Health at the University of Washington. Baeten trained in Kenya as an M.D./Ph.D. graduate student and did much of his early research with the Mombasa Cohort.
“Working with the Mombasa Cohort … was foundational to everything I’ve done since,” said Baeten, who went on to tackle HIV prevention globally, leading large studies showing the efficacy of pre-exposure prophylaxis (PrEP) and the dapivirine vaginal ring against HIV transmission. The Mombasa Cohort is “very attentive to questions that were meaningful to the populations and communities” in which it is being conducted, Baeten explained, and the science has been done in “ways that were an investment in the community — and the population and the city and the country, and the first benefits were directly back to Mombasa and to Kenya and the women who were in the cohort.”
Overbaugh, then at the University of Washington, started the Mombasa Cohort with UW colleague Dr. Joan Kreiss. Kreiss, an epidemiologist, had been studying patterns of HIV transmission in Kenya. In the early 1990s, the National Institutes of Health put out a call for researchers to establish cohorts of people to participate in HIV vaccine trials — but Overbaugh and Kreiss suspected that vaccines were still far in the future. Instead, they took the opportunity to set up cohorts to answer basic questions about HIV transmission.
To set up cohorts of people who were HIV-negative but at high risk of acquiring the virus, Kreiss reached out to two colleagues, Dr. Kishorchandra Mandaliya, a provincial pathologist for Kenya’s Coast Province, and Dr. Jeckoniah Ndinya-Achola at the University of Nairobi. One cohort, a group of male truck drivers, lasted more than seven years but ended due to the difficulty of keeping in touch with participants whose jobs had them crisscrossing the African continent.
For the Mombasa Cohort, the scientists partnered with a clinic that offers sexual health care to female sex workers in Mombasa. Women who agree to participate in Cohort studies receive their normal health care plus a few extra tests. And while individual women may drop in and out of the Cohort, the Cohort itself has endured since the first participants were enrolled in February 1993.
That makes it the longest continuously running African cohort aimed at assessing risk of HIV infection, said Dr. Scott McClelland, who took over as a principal investigator of the Mombasa Cohort and the site leader of the UW/University of Nairobi Mombasa HIV/STD Research Site in 2002. While the similarly long-lived Rakai Cohort at Johns Hopkins University had a two-year break in funding, Kreiss, Overbaugh, and McClelland sustained their Mombasa Cohort with a series of individual grants that spanned a variety of research questions, from which other infections or health practices may increase susceptibility to HIV to understanding the mechanisms of HIV transmission between people.
The team also built into their grants support for impressive scientific exchange. U.S. epidemiologists like Baeten and McClelland conducted studies in Kenya, and many Kenyan researchers have trained in the labs of their collaborators in Seattle. Dr. Bhavna Chohan, now an acting professor at UW and a senior scientist at the Kenya Medical Research Institute, began as the Mombasa Cohort research laboratory manager in 1993 and completed her Ph.D. in virology with Overbaugh at Fred Hutch. Kenyan doctors and nurses trained in the U.S. as well, and American doctors and nurses trained in Kenya.
It has been an “easy and balanced exchange in a way that’s a model for all global health research,” said Baeten, who joined Kreiss’ team in 1997 and conducted two years of HIV research in Kenya while working toward a Ph.D. in public health.
Mombasa is a “really fertile place to do really complex, multidisciplinary work,” he said. “There’s a really deep understanding of heterosexual transmission, especially to women. … There’s clinical infrastructure, scientific infrastructure; public health science, lab science; political will to do the work — the whole package.”
This allowed the Mombasa Cohort to make lasting contributions to our understanding of HIV transmission and lay the groundwork for critical interventions, said Baeten.
“I think the work in Mombasa has in some way has touched on every important intervention that has been done in HIV prevention,” said he said.
When Overbaugh helped initiate the Mombasa Cohort, she was primarily interested in examining what happens when HIV jumps from one person to another.
HIV evolves rapidly, creating a hugely diverse population of individual HIV variants circulating within a single patient. What wasn’t clear in 1993 was whether new infections occurred when many variants passed from the original host, or if only a few made the jump and initiated an infection in a different individual. Based on previous work with other host species infected with related viruses, Overbaugh suspected that new infections start with only a few variants, meaning that HIV faces a bottleneck during transmission.
Overbaugh knew that to answer this question, she would need to step outside the lab and study viruses circulating in people — an approach that was not widely practiced by basic sciences at the time.
“[I thought] if we were going to focus on vaccines, prevention and do biological studies with HIV, we had to actually be studying the right viruses,” said Overbaugh. “And at the time we did that, that wasn’t the way people thought about it; they just took any HIV off the shelf.”
Many strains of HIV that scientists stored “on the shelf” for research purposes are “lab-adapted,” meaning they had evolved under laboratory conditions, not the human conditions under which HIV evolves in the world. Studying lab-adapted strains has led researchers to erroneous conclusions, noted Overbaugh.
For example, lab-adapted HIV strains are easy for HIV-specific immune proteins to block in Petri dishes. Until scientists began investigating HIV strains from people, they expected immune proteins in our bodies would also easily neutralize the virus. But they don’t, which is a critical insight for anyone attempting to design a vaccine against it.
Overbaugh and her team did find that HIV faced a bottleneck as it passed from person to person. In newly diagnosed people, they found that only one or a few variants had initiated the infection. Her team showed that infection with more than one genetic variant is linked with risk factors such as hormonal contraceptive use and presence of other sexually transmitted diseases and leads to higher levels of virus.
Researchers in the HIV field eventually came around to Overbaugh’s way of thinking, but HIV has so far evaded a clear explanation as to what shapes the transmission bottleneck. Though her team’s research focus has largely shifted away from this question, “People are still looking; this is not a solved problem,” Overbaugh said.
We rely on our immune systems to shield us from infection. Generally, once we’ve experienced an infection, our immune response to that infection will keep us from acquiring it again. Once you’ve had chicken pox — or been vaccinated — you don’t have to worry about picking up a new chicken pox infection from a slightly different strain. Your immune response triggered by the first exposure will protect you.
But Overbaugh and her team began to suspect that it doesn’t work this way for HIV. DNA sequences from viruses they’d isolated as part of a different study in Kenya suggested that sections of the HIV genome had recombined — something that could only happen if a person was infected with more than one strain.
A few case studies reported by others also suggested that even once infected with HIV, a person could acquire a second HIV infection — a situation referred to as superinfection.
Chohan, the Kenyan scientist who trained with Overbaugh, partnered with another graduate student, Anne Piantadosi, to examine the prevalence of superinfection in the women of the Mombasa Cohort as her Ph.D. thesis project. The large number of women in the Mombasa Cohort allowed the scientists to specifically compare the risk of a first HIV infection to superinfection among many people, instead of merely describing the phenomenon in a single individual, said McClelland.
Chohan found that many of the women who were infected with HIV a first time often could still acquire HIV a second time, suggesting that HIV infection — and the immune response to it — provided little protection against infection with a new strain.
Her findings, borne out by further work by Overbaugh’s group, raise questions about the deficits in the immune system that leave already-infected people vulnerable to further infection despite an active immune response to the initial HIV exposure.
“It’s telling us that the immune response to HIV is never good enough,” said Overbaugh. She and McClelland contend that this is important to keep in mind as scientists attempt to develop an HIV vaccine. Right now, most researchers are focused on creating vaccines that stimulate antibodies, immune proteins that recognize HIV and block its ability to infect cells. But her lab has shown that in humans, even people with high levels of antibodies can acquire a second HIV infection.
What infection with two strains of virus might do is prompt a broader antibody response capable of blocking a wider range of HIV variants, said Overbaugh. She is currently testing the idea that triggering immune responses to more than one HIV variant could produce more protection against the virus.
Researchers working with the Mombasa Cohort have always focused on questions with particular relevance to the women participating in their studies, said Overbaugh.
Some of the questions about HIV susceptibility that researchers explored in the early years of the Cohort “sound dated [now] because we knew so much less about HIV transmission,” said McClelland. “We were doing genital HIV shedding and exploring things like how hormonal contraceptives or presence of STIs or vaginal infections influence levels of genital HIV shedding.”
But these questions led to important answers. The Mombasa Cohort was one of the first to reveal that use of the injectable hormonal contraceptive Depo-Provera was associated with increased risk of HIV infection. “It was because of that very strong work that other people in other places tried to explore that potential association,” said Baeten.
Now, 20 years of studies have suggested that Depo-Provera may increase women’s HIV susceptibility by up to twice the risk of women who choose other contraceptive options, said Baeten. He’s now a part of the Evidence for Contraceptives and HIV Outcomes (ECHO) trial, a larger ongoing trial that aims to definitively pin down whether Depo raises HIV risk.
Work out of the Mombasa Cohort was also among the earliest to link genital tract infections, like sexually transmitted diseases or bacterial vaginosis (BV), with increased HIV risk. That “is really where [the Mombasa Cohort] has been on the cutting edge,” said McClelland.
In collaboration with Fred Hutch’s Dr. David Fredricks, McClelland recently published what may be one of the last prospective studies to come out of the Mombasa Cohort. In research conducted over a decade and folding in data from several HIV cohorts, team was able to link seven specific bacterial species to increased HIV risk.
“Ultimately identifying there are just a handful [of bacterial species] that we find are particularly strongly associated with women’s risk of acquiring HIV, I think creates a new set of targets to think about how we might modify risk for these women by changing their vaginal microbiota,” said McClelland.
The reason that scientists working with the Mombasa Cohort may have to pivot away from studies assessing risk of new infections is that the incidence of infections in women participating in the Cohort is now incredibly, wonderfully low — less than 1 percent per year. This is a dramatic drop from the incidence of 16 percent per year seen in the beginning of the Cohort.
Even before anti-retroviral therapy (ART) and PrEP came onto the scene, the counseling, health care and frequent STI and HIV screening provided by the clinic were already helping to decrease incidence in women participating in the Mombasa Cohort, said McClelland. He also worked to make it one of the first places in Africa where women in sex work could access ART for free.
When ART first came on the scene in the late 1990s, it cost upwards of $16,000 per person per year — far beyond the scope of a research study, McClelland said. But in 2004, a grant through the Bill & Melinda Gates Foundation provided McClelland enough funding to treat 100 women for two years.
He recalled “starting people on treatment when there had been none, seeing people who had really given up on living, and were within three to six months, empirically, of being likely not to survive. And seeing them realize they were going to survive, and rethink going back to work, taking care of families and things like that — it was incredibly exciting.”
More recently, he and his team were able to show that for every 1 percent increase in ART coverage in a community, the risk of acquisition in the sex workers drops 3 percent.
“I fully expected to see an effect, but the magnitude was striking,” McClelland said. “It really reinforces the idea that treatment is prevention.”
The Mombasa Cohort helped change the landscape of HIV and HIV research, said Baeten.
“Certainly in 1997 when I started it was a disease with limitless fear, and so much opportunity to make change,” he recalled. “Now there’s the opportunity to have impact with change — in part because of the work done with the women of the Mombasa Cohort.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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