|
Following Trail Of the Monkeys FOR AT LEAST 17 years it has been known that the epidemic form of HIV has less deadly, close cousins, found in people, apes and monkeys. What is still not known is why these viruses' impacts are less devastating. Somewhere in the solution of that puzzle, scientists insist, lie clues that could be vital to the development of an effective vaccine. The virus that has infected, cumulatively, some 60 million people and killed 23 million since 1981 is called HIV-1, or the human immunodeficiency virus type 1. It has an apparently less deadly human cousin called HIV-2, which is almost exclusively found in West Africa. And in monkeys there are simian immunodeficiency viruses types 1 and 2, or SIV-1 and SIV-2. While HIV-1 is spreading rapidly among humans worldwide, HIV-2has not - a finding that confounds scientists. SIV-1 is even more puzzling, for its level in the blood of wild African green monkeys reaches billions of viruses per drop of blood - yet it produces no apparent ill effects. SIV-2, likewise, infects sooty mangabeys without doing any apparent harm. But when those SIVs are given to certain other primate species from other areas - the Amazon or Asia, for example - the animals develop AIDS and die. That indicates that the SIVs have been infecting African monkeys for thousands of years and have evolved to a stage where they can grow and reproduce without destroying their primate hosts. The Asian and American monkeys, however, have never been infected with either SIV species except in the laboratory, so the viruses prove deadly. When HIV-1 is injected into chimpanzees - human beings' closest genetic cousins - the animals become infected but usually remain unharmed, showing no sign of disease. Only one research group in the world, the Yerkes Primate Center outside Atlanta, has caused AIDS in chimpanzees. Dr. Shawn O'Neill and his colleagues injected 10 chimps with a powerful laboratory strain (not found in nature) of HIV-1 about 15 years ago. In 1996 one chimp developed symptoms similar to human AIDS. Last year, two more from that group of animals took ill. One chimp seems to have cleared HIV from his body through unknown means. And the remaining animals continued to show no outward ill effects. "Aside from humans, chimpanzees are the only animals that are consistently susceptible to HIV infection," O'Neill says. So far he hasn't discovered any explanatory differences between the chimps with AIDS and those that have remained symptom-free. But he has noticed a big difference between the AIDS chimps and humans who manage to survive with the disease for many years. It's a puzzling difference. The long-term surviving AIDS chimps do not appear to mount an enormous immune response against HIV. Yet the immune systems of long-term human survivors seem to be in a fully activated state of war. Why, scientists ask, should not a waging immune response battle against HIV be a good thing? The answer must have something to do with how HIV manipulates the human immune system. And that, in turn, could have implications for vaccine development. The role of a vaccine is to stimulate an immune response - and one lesson here is that stimulating the wrong sorts of immune responses might be more dangerous than no response at all. SIV-1, the simian equivalent of HIV-1, is found naturally in African green monkeys and is the source of another puzzle, says Dr. Ron Desrosiers of the New England Primate Research Center. Levels of the virus in their blood are extraordinarily high - even higher than is usually seen in humans with AIDS. And that indicates that a high viral load, or amount of viruses in the blood, isn't always a bad thing. "This is an important clue," says Desrosiers, noting that multiple factors may contribute, "and they may be difficult to sort out." Desrosiers is betting that one key factor is sugar. Both HIVs and SIVs hide from the animals' immune systems by coating themselves in sugar molecules. Desrosiers has found mutant SIV-1 strains that are unable to coat themselves in the protective candy and are quickly destroyed by antibodies after injection into usually vulnerable macaques. Clearly the presence of the [sugar] affects the ability of the host to mount effective antibody responses," Desrosiers said in a keynote speech at the Human Retrovirus Conference earlier this year. "I think that antibodies mounted against wild-type SIV in monkeys . . . are not effective. These antibodies are not able to do their job largely because of the way the virus has constructed and coated its envelope." Another factor that may explain the monkey results, notes Dr. David Ho, director of the Aaron Diamond AIDS Research Center in Manhattan, is that when humans have high viral loads, their crucial immune system cells die off, usually in numbers that correlate closely with the size of the attacking HIV population in their bloodstreams. But the green monkey can have far greater numbers of SIV-1 in their blood without experiencing any immune cell destruction. "So there is a disconnect we don't understand," he said. This disconnect grows more puzzling when HIV-2 is considered. People with HIV-2 seem to live years longer without developing AIDS and, once ill, the progression to death is slower than with HIV-1. Further, the virus seems to be less transmissible from person to person. Why? Most clues, says Dr. Kevin DeCock of the Centers for Disease Control and Prevention, point to viral load. Yet this is seemingly at odds with the viral load conclusions reached in the monkeys. Why is there no HIV-2 pandemic? Probably largely because of the different behaviors of HIV-2 in relation to viral load," DeCock says. Based on surveys he conducted in West Africa, DeCock concludes that HIV-2 never reaches the same millions-of-viruses-per-drop-of- blood levels in people with HIV-1. Fewer viruses, he argues, means less HIV to transmit to other people and fewer killers attacking cells and leading to AIDS. "It is related to viral load, but the question is, why is the viral load lower?" said Dr. James Curran, dean of the Rollins School of Public Health at Emory University in Atlanta, noting that viral load in humans is, somehow, linked to the overall virulence of the virus. "And there are similar differences among HIV-1 strains. "For example, the Kimberly Bergalis strain connected to that Florida dentist killed all of those patients within two to three years after infection," he said, compared with the typical 10 to 12 years seen with most HIV-1 strains. A hallmark of all SIVs and HIVs is the ability to hijack the
chemicals in human cells to their advantage. It's possible that these variabilities in virulence and transmissibility are due to
the viruses' inabilities - or abilities - to make use of Some of those would-be chaperones appear to be absent in monkey cells. Dr. Wayne Koff, scientific director of the International AIDS Vaccine Initiative, ranks these SIV and HIV-2 puzzles at the top of his list of priorities. "The reason they haven't been answered," Koff insists, "is nobody at the [National Institutes of Health] has been under the gun to answer those questions. You need to get six to eight of the best minds in immunology together to solve this problem. Period. "It may turn out that even if we have the answer, it's not going to lead anywhere. But it sure as hell isn't going to help if we don't have the answer . . . So hire somebody that rides herd over a group until it gets them answers. It's not going to happen with business as usual." A final problem for would-be solvers of these mysteries is the monkeys themselves. Sooty mangabeys are an endangered species, so research on HIV-2 is difficult to perform. The most vulnerable species, in terms of SIV-1 and -2, is the rhesus macaque, but they, too, are in short supply. Once readily available from dealers in India, macaques are now closely protected by the Indian government. Most of the rhesus supply in the United States has been purchased by the Merck pharmaceutical company. African green monkeys, in contrast, are widely available and easy to breed. But few researchers are studying that species, despite the clear need to understand how they tolerate SIV-1 infection. Chimpanzee research is out of the question, as the animals are endangered and extremely expensive. |