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Additional articles in this series.
NAIROBI, KENYAIn this city's Pumwani slum, everything seems inverted. Pumwani is one of the Kenyan capital's red-light districts, but the action happens during the day. After dark, it gets too dangerous even for prostitutes. Then there's the way the women advertise: no hip-high skirts or brazen busts. Instead, says Joshua Kimani, a charismatic young doctor who runs a research clinic for sex workers, a prostitute is "whoever sits outside their doorway looking clean."
But the most profound turnabout centers on women like Joyce, who lives in a room hardly big enough for her bed. Joyce, who asked that her real name not be used, came to Nairobi from Tanzania. With three children to feed, she turned to prostitution within a year. That was 1983.
No one knows exactly when HIV entered Nairobi. But in 1985, Canadian researcher Frank Plummer was studying gonorrhea and chlamydia among Pumwani sex workers, and almost as an afterthought he decided to add an HIV test. Two-thirds of the women tested positive. He shifted his focus to HIV.
Joyce was one of the lucky uninfected womenin fact, her luck was nothing short of astonishing. Fourteen years have passed since her original HIV test, and she has spent half those years servicing up to 10 johns a day. Yet she has remained HIV-negative even as the percentage of infected prostitutes topped 90 percent. She contracted other STDs, proving that her partners didn't use condoms and that she was almost certainly being exposed to HIV. But Joyce didn't get it.
Joyce was certainly unusual, but not unique. Indeed, Plummer made a curious discovery: If a sex worker didn't contract the virus after five years, she was unlikely ever to get it. The simplest explanation was that women like Joyce were resistant to HIValmost uninfectableand that's why these sex workers electrified the scientific community. They were, in the understated language of researchers, "multiply exposed but uninfected."
Prostitutes have been the scapegoats for AIDS in Africa, where the disease is spread mainly by heterosexual sex, and where men blame sex workers for bringing down AIDS. But, in the richest of ironies, Joyce and other prostitutes have provided researchers with valuable clues to the intricate workings of the immune system, and especially how it might be able to fend off the virus. In fact, the knowledge researchers gained from these women has been translated into a promising vaccine that is about to be tested in humans. The scapegoats of Africa's epidemic just might turn out to rank among its saviors.
Only a vaccine can end the AIDS epidemic.
The powerful new AIDS drugs, besides being too expensive for developing countries, do not cure the disease. In America and Europe, drug resistance and severe side effects are undermining the treatment of more and more patients, and the notion that HIV could be purged from the body has been shattered. The virus, which integrates into a patient's own DNA, appears to persist for life.
In theory, behavioral changes could stop the epidemic, and many Africans look to Uganda for hope. Ugandan president Yoweri Museveni aggressively confronted the epidemic, and infection rates in some urban areas have declined dramatically since the early 1990s; one surveillance site found that the prevalence of the virus has fallen by half. Yet even at that site, more than 13 percent of pregnant women are still infecteda huge pool of HIV-positive people. While education certainly can save millions, the fact is that behavioral change has never managed to halt the epidemic, not even in wealthy countries.
But vaccination has eradicated one diseasesmallpoxand is on the verge of eliminating a secondpolio. Ugandan researcher Roy Mugerwa, principal investigator of Africa's first AIDS vaccine trial, says, "We have learned from history that the only way to halt epidemics is with a vaccine."
Vaccines do not fight off infection; instead, they teach the immune system to recognize and attack the microbe. The world's first vaccine, for smallpox, was the cowpox virus, which causes only mild symptoms in people but primes the immune system for smallpox. Salk's polio vaccine was simply a killed polio virus. Technology has advanced, but the principle remains the same as when the ancient Chinese used to blow pulverized smallpox scabs through a bone into people's noses: Train the immune system with a dummy virus.
But can the body be taught to fight off HIV? There was a time when many scientists came close to despair, and many still harbor doubts. After all, AIDS attacks the immune system itself, and it kills almost everyone it infects. There were always people who recovered from smallpox, and there were many more who never even showed symptoms because they fought off the virus so quickly. But the more scientists learned about the natural history of AIDS, the more it seemed that everyone infected would succumb and that no one could repel the virus.
This is why the Pumwani prostitutes are so important. It's also why "people didn't believe us in the beginning," recalls Omu Anzala, one of the researchers who studied the Pumwani women. Had the sex workers really come in contact with the virus? They certainly didn't test antibody-positive, the classic trace of an infection. So maybe, despite all their johns, they had never encountered the virus.
But the virus leaves other traces. The immune system has two main arms: antibodies, which attack viruses floating free in the bloodstream, and cytotoxic T-lymphocytesor killer T-cellswhich destroy the body's own cells that have been infected. Like antibodies, killer T-cells are specific to one microbe, so they, too, are a kind of fingerprint.
What happens is that an infected cell displays on its outer membrane fragments of the virus called epitopes. Killer T-cells that recognize these particular epitopes destroy the infected cell. What's more, the immune system clones millions of killer T-cells that are specific to those epitopes, in order to wipe out all the cells the virus has infected. So, high numbers of HIV-specific T-cells indicate that the virus was present.
Oxford researcher Andrew McMichael is one of the world's leading experts on the killer T-cell. McMichael and his colleague Sarah Rowland-Jones had studied multiply exposed yet uninfected sex workers in the West African nation of the Gambia, and many of them had elevated numbers of HIV-specific killer T-cells. But in the world of the multiply exposed, the Gambian sex workers couldn't hold a candle to the Pumwani prostitutes. They were the acid test.
Plummer's team had found evidence of HIV-specific killer T-cells, but many scientists weren't convinced. Collaborating with Plummer, the Oxford researchers verified the findings, banishing virtually all scientific doubt: The women really had been exposed to HIV, and their bodies had mounted a defense with killer T-cells.
Could those cells be the key to protection?
As scientists learned more about HIV's initial assault on the body, it became clear that the immune system always mounts a vigorous counterattack. In fact, what happens in the first few weeks after infection is nothing short of extraordinaryand it bolsters the current consensus that killer T-cells are critical to warding off HIV.
What typically happens is this: The surfaces of certain cells in the body are studded with two molecules, named CD4 and CCR5. If the virus chances upon such a cell and binds to these molecules, then, like a burglar picking a lock, HIV gains entry, commandeers the cell's DNA, and forces it to churn out as many as 10,000 new viruses. These are ejected from the cell to float in the body, waiting to enter new cells.
Within 48 hours, swarms of viruses have advanced from the site of infection into the lymph nodes, where HIV's favorite immune-system cells abound. In as little as three days, the virus has infiltrated certain long-lived cells where it can hide out during years of ferocious medical assault and still emerge to rekindle the infection. By the 10th day, HIV has usually spread to the brain, spleen, and gut. At this point in the invasion, the amount of HIV in the blood soars to almost unbelievable levels: A single milliliter of blooda mere dropletcan be teeming with as many as 95 million viruses.
Then the immune system rallies. The body produces millions of HIV-specific killer T-cells that attack infected cells and also excrete special molecules that can paralyze HIV. Antibodies against the virus won't appear in the blood for about two more weekssometimes not for a few monthsand they seem to have little effect. It is the killer T-cells that appear to suppress the virus.
Yet they don't eliminate it. Instead, the virus and the immune system become locked in a pitched battle that lasts for years. Eventually, for reasons that are still not understood, HIV overwhelms the immune system, rendering the patient vulnerable to whatever diseases come along.
Those initial days of infection, when the body becomes saturated with virus, are the key to a vaccine, McMichael believes. Killer T-cells are "always chasing the virus," he says, "and the virus is always one step ahead. But if a person is vaccinated, then the immune system starts out ahead."
So what McMichael and his team have done is construct a vaccine made from the DNA of epitopes that killer T-cells recognize. He's made sure that these virus fragments come from parts of HIV that don't mutate and so can't change to escape the T-cells' attack. Some of the epitopes in the vaccine are ones targeted by killer T-cells of the exposed but uninfected Pumwani prostitutes. "The vaccine," says Plummer, "was built in part around these women."
After safety trials in England starting early next year, the vaccine will go into trials in Nairobi. Maybe a vaccinated immune system can eliminate the virus before it gains a foothold. Or, barring that, maybe the vaccine could help the body suppress the virus to such low levels that it would be hard to transmit and never cause disease.
Selina, not her real name, blocks out the difficult parts of her life. She claims, for example, that she cannot recall the first time she had sex for money. But she revels in the scraps of good fortune that come her way, such as the fact that she never got HIV. Like Joyce, she had been in Plummer's original 1985 cohort, and like Joyce she didn't get infected. She bragged that she was immune. But today, when asked if she used to think she was invulnerable to the virus, she answers in a non sequitur, saying that she has to be careful because some men remove their condoms "in a tricky way."
The life of prostitutes in Pumwani is hard. When they contract HIV, they progress to full-blown AIDS in an average of just four yearsfar less time than Kenyan women who aren't sex workers, not to mention First World women. The prostitutes, says Plummer, live "incredibly violent" lives. In 1996, Selina was raped repeatedly. At that point she had tested HIV-negative for 11 years. But shortly after the rape, she tested positive. She has already suffered a variety of AIDS-related illnesses and lost more than 10 percent of her body weight. The veins on her forearms are prominent, running like long ridges down the smooth landscape of her skin. Yet Selina has staunchly refused to be told the results of her test. Kimani explains, "She can't come to terms with the fact that she thought she couldn't get HIV and now she has."
There are a few others like Selinamultiply exposed, persistently negative women who suddenly have become positive. Plummer and Kimani think that in Selina's case, the stress of the rape might have weakened her immune system. But the other women who have belatedly turned positive seem to have another risk factor: stopping prostitution.
High levels of killer T-cells are not normally maintained for long periods. They arise in response to an invading microbe, then subside. So perhaps what's keeping the women immune is constant, low-level exposure to HIV from their johns. When the women take a vacation, their killer T-cells wane, leaving them vulnerable to the virus.
What does this mean for a vaccine? "It's not good news," says Plummer. After all, one would hope that immunity lasted forever, or at least for many years. If frequent booster shots are required, a vaccine would be unaffordable where it's needed most: in the developing world.
But McMichael has a different take on the newly infected women. Kimani found that resistance runs in families, suggesting a genetic trait. Such traits have been found in other people; some Caucasians, for example, have a mutation which makes their cells impregnable to the most common strains of HIV. But the fact that the Pumwani women can get infected is actually "good news," says McMichael. "Not for those women, of course, but it is good news for a vaccine because it means they don't have some special, undetected genetic immunity that a vaccine couldn't induce."
By far the biggest obstacle to an AIDS vaccine is the virus itself. For one thing, HIV has many different strains, called subtypes, and the major one in the United States and Europeand hence the one most used in most candidate vaccinesis different from the dominant subtypes in Africa. No one knows if a vaccine designed against one subtype will protect against infection by a different one.
Then too, people's immune systems are different, composed of various "HLA types." Even if infected with the same strain, people often display different viral epitopes on the surface of their cells. These differences tend to correspond with ethnicity, so a vaccine that protects most whites might not be as effective among Asians or Africans.
McMichael has tackled these problems by making his vaccine out of fragments of the HIV subtype most common in Kenya, subtype A. In addition, he has included enough epitopes to cover probably every HLA type in East Africa. Still, McMichael's vaccine contains only 44 epitopes, plus a whole viral gene. Are these enough? And are killer T-cells truly the key to protection?
Most of the uninfected prostitutes appear to produce a special antibody in the place where HIV first enters them: the mucosal tissue of their vaginas. So, should a vaccine induce site-specific antibodies? There are other experimental vaccines that attempt to do exactly that.
No one knows the answers to these questions, but Africans are not waiting for the West to solve the problem. "I lost my own brother to AIDS two years ago," says Anzala, who has dedicated many years to studying the Pumwani sex workers' immune systems. "That really devastated me, because with all the knowledge I had. . . . " His voice trails off; then he snaps back and adds, "We can't wait for something to come from the U.S. No. We have to participate."
Indeed, African scientists are actively contributing to the research, providing ideas and laboratory research, pushing scientists to put candidate vaccines into trials on their continent, and insisting that the world develop vaccines that are likely to work against their subtypes of HIV. Uganda is already hosting the continent's first human trial of an AIDS vaccine, and Ugandan researchers are conducting the sophisticated laboratory analyses needed to evaluate the trial. South Africawhich accomplished the world's first successful heart transplanthas the most developed biomedical research capacity in Africa. President Thabo Mbeki has declared an AIDS vaccine a top priority, committing government funds to a soup-to-nuts research effort. "We're not just trial sites in Africa," says Quarraisha Abdool-Karim, a veteran South African AIDS researcher. "We have an intellectual contribution to make."
While the Africans are pushing as hard as they can, AIDS scientists around the world are also putting vaccines high on the agenda. The U.S. National Institutes of Health, which dwarfs any other medical research agency in the world, and which spends more than a billion dollars on AIDS research alone, used to give vaccine research less than 10 percent of its AIDS budget, less than any other category of HIV research. But over the last three years it has ratcheted up that percentage, and it has brought in Nobel laureate David Baltimore to lead its effort. Whereas the mood was once pessimistic, most scientists now believe a vaccine is possible.
But even if the scientific obstacles are overcome, another hurdle will remain.
Vast, impoverished, and riven by civil war, the Democratic Republic of the Congo is the hardest place on earth to conduct a vaccination campaign. But three times this year, thousands of health workers went out into the countryside, squirting the life-saving pink liquid into the mouths of millions of Congolese babies. In a village outside the town of Mbuji-Mayi, proud mothers held up their vaccinated babies as the whole village celebrated the immunizations. Despite war, the World Health Organization predicts that within a year, the Congo and the world may be polio-free. This is the dream of AIDS-vaccine workers.
But it is also the nightmare, because despite a cheap and effective vaccine, polio is being wiped out only now, about four decades after it was banished from America. Once an AIDS vaccine is developed, will Africa have to wait 40 years for it?
If the vaccine based on the Pumwani prostitutes works, Africa will get it soon. That's because its development is sponsored by the International AIDS Vaccine Initiative (IAVI), which is laying the groundwork for something that has never happened before: simultaneous delivery of a vaccine to the developed and developing worlds.
IAVI president Seth Berkley, who worked in Uganda during the early days of the AIDS epidemic, is a man in perpetual motion. He has lobbied the World Bank, the EU, the G-7, and any other deep pocket that will listen to create a fund for distributing an AIDS vaccine in the developing world. In addition, IAVI is making sure the vaccines it bankrolls will be available in poor countries.
Berkley has convinced Bill Gates to give his organization $26.5 million and the British government another $23 million; IAVI invests these funds in promising vaccines, fast-tracking them through the pipeline. "We are like a venture-capital firm," Berkley says. "But instead of demanding 50 percent of the profits, we want access for the poor."
Essentially, IAVI negotiates agreements that give the manufacturer the option to make the vaccine affordable for developing countries. But if they don't, says Berkley, "We retain a series of rights that allow us to get the vaccine out there."
At the Pumwani clinic, Kimani, the young doctor, says, "We promised the women that anything that came out of the research will benefit them. And they are already asking about the vaccine." In fact it will be years before the vaccine is ready for large-scale efficacy trials, let alone before researchers know whether it actually protects people. Even when pushed, science crawls.
Meanwhile, Kimani explains what happens as the women approach death. "When they are clearly deteriorating, we call them in. They ask, 'Am I not doing well?' And we say, 'Maybe it's time to go home to the village.' " Kimani pauses. "We have money we can give them to go home to their family." That statement sinks in, and then Kimani saysshouts, almost"We desperately need a vaccine!"