The Scientist 13[16]:7, Aug. 16, 1999

News

AIDS Vaccine Researchers Turn From Chimps To Monkeys

By Paul Smaglik

Defining the usefulness of chimpanzees for AIDS research may be more like sticking one's hand into a hornet's nest than reaching into a barrel of monkeys. On a superficial level, monkeys appear to make the easiest AIDS model, while chimpanzees would seem to make the best. But on a practical level, using a more common primate rather than an endangered species has its merits too--which may explain why the National Institute of Allergy and Infectious Diseases (NIAID) appears to be moving away from chimpanzees to monkeys for AIDS vaccine studies.

This past March the National Institutes of Health quietly stopped funding the monitoring of about 100 HIV-infected chimps at the Coulston Foundation in Alamogordo, N. Mex. Next year, the NIH will likely discontinue another contract that funds breeding and managing of chimpanzees at five primate centers. When that contract runs out, NIH will likely consolidate management of chimps from five sites to two not-yet-chosen sites.

Steven Bende, who coordinates funding for preclinical AIDS vaccine studies at NIAID, notes that chimps and AIDS present a "logistical problem." While chimps are the only known animal other than humans that can get infected with HIV, those infections seldom develop into full-blown AIDS, because the virus replicates differently in chimp cells than in human cells. In the few cases that have progressed to AIDS-like illness, symptoms appeared after 10 or more years. Bende also notes that chimpanzees are both expensive and endangered. "The chimpanzee model doesn't get a lot of support in the scientific community because of those facts," comments Bende. He emphasizes that lack of scientific merit--not formal NIAID policy--has driven the move away from chimps; no current contracts exist for chimps in AIDS-vaccine-related studies.

Monkeys, on the other hand, are more common and less expensive to house. They also show AIDS-like symptoms much sooner after infection. Still, because monkeys get infected with SIV rather than HIV, they, too, aren't a perfect model. "SIV in monkeys is not the same as HIV in humans," Bende admits.

Thomas Insel, director of the Yerkes Regional Primate Center, Lawrenceville, Ga., agrees with the apparent policy reversal: "I just don't see much coming out of the chimp work that has convinced us that that is a particularly useful model." He cites the time it takes chimps to develop AIDS-like symptoms as particularly problematic--especially since pressure exists to find a treatment for the fatal illness as soon as possible. "[An animal model] that takes 12-14 years to develop doesn't sound to me to be ideal." He also claims that 15 years of AIDS research in chimpanzees has produced little data relevant to humans. "I can't tell you what it is that those studies have given us that has really made a difference in the way we approach people with this disease," Insel, who favors monkey models, comments. "I wouldn't say that about the monkey work."

Mohammad A. Javadian, director of research at the Coulston Foundation, disagrees. "The most suitable primate for an AIDS vaccine animal model is chimpanzee," Javadian notes. "[They] are the only animals that can experimentally be infected with HIV." He also disagrees that no relevant AIDS findings have come out of chimp work. One 1997 study showed that a DNA vaccine protected two of four chimps from a nonpathogenic strain of HIV, he points out.¹ Since then, scientists have used that same vaccine on two HIV-infected animals as a therapeutic agent. "In one of them, the viral load dropped to undetectable levels," Javadian says. Chimps who were protected from infection with the DNA vaccine and the ones treated with the vaccine after infection are still healthy, Javadian notes.

But in some ways the success of that experiment illustrates the trouble with chimps. Because of cost and difficulty in handling the primates, the study was limited to a few animals. That small sample makes it difficult to translate the results to humans. "A few animals per study arm is not sufficient to provide statistically significant results," comments Bende. Javadian agrees that size is an issue--but only because of cost. More chimpanzees could be bred and raised if NIH deemed the animals a priority. Each chimpanzee in a study requires a minimum of $100,000 worth of care, Javadian notes.

Mark Goldsmith, an AIDS researcher at the University of California, San Francisco, calls chimpanzee cost a "fundamental issue." "The cost substantially decreases the size of any particular study, and it also limits the number of investigators to perform such studies," Goldsmith explains. "And science, of course, depends upon competition and overlap and reproduction and enhancements and incremental advances of one scientist on the work of another. If there are only three or four scientists around the country who have the resources and access to a primate facility, obviously the type of progress that can be made is constrained." Goldsmith hopes to overcome that constraint by developing a cheap, easily bred small-animal model, perhaps in rat, rabbit, or mouse. But no viable one has yet been produced.

Researchers may also be reluctant to use chimpanzees because of animal-rights issues surrounding the endangered species. Javadian notes that several activists have produced Web sites denouncing the Coulston Foundation's treatment of chimpanzees. However, Bende and Insel deny that the pressure of animal rights groups is preventing more widespread use of the animals. The lack of scientific merit remains the main obstacle, they insist. "If we really felt that using chimps was going to get us to where we needed to be in terms of ending this epidemic, the animal rights stuff would have almost no impact at all," Insel states.

David Weiner, University of Pennsylvania AIDS researcher, notes that researchers who do use chimpanzees consider concerns that are also relevant to animal rights activists. For example, when Weiner and colleagues challenged the chimpanzees in the 1997 Nature Medicine DNA vaccine study, they used a nonpathogenic strain of the virus. "There's a reticence on [the part] of researchers to use a pathogenic challenge on these models," Weiner notes. "We have to be certain that we're going to prevent infection."

Still, despite those precautions and the initial success of the DNA vaccine experiments, Weiner notes that he's been having a difficult time getting funding for more chimps--a trend he suspects will continue as chimpanzee monitoring, care, and maintenance contracts continue to expire. He concedes that working with other primates, like the small and abundant rhesus macaque, has its advantages. "You can do more animals," he notes. But testing vaccines and drugs in more animals may not be helpful in the end if those animals don't closely recapitulate humans.

Drastically reducing the chimpanzee population could also turn out to be shortsighted. Weiner notes that now most experimental vaccines attack a single component of the virus--usually one of the viral envelope proteins. That condition can be approximated in monkeys by using SHIV--a chimeric combination of SIV and HIV--or other transgenic tricks. But a successful vaccine may need to attack more than one component of the virus. If such a vaccine is developed, researchers may need to once again turn to chimps, because SIV, SHIV, and HIV all differ beyond the envelope protein. If a multicomponent vaccine emerges, chimps may be "clearly a strength," Weiner notes.

Researchers are improving SHIV and working to build small-animal models for AIDS. But both SHIV and small-animal models require refinement before they render primates irrelevant. "I don't think either one is where it needs to be yet," Weiner comments. Weiner, Insel, and Bende agree that the problem with all animal models for AIDS is that they are just that: models. Success in any animal model does not necessarily predict success in humans, Weiner notes.