As a poet wrote, "The proper study of mankind is man." But when itcomes to diseases, studies properly rely on animal models.Until gene transfer made it possible to convert mice into mimics ofdiseases, research pathologists had to rely on luck _ such asdiscovering a mouse mutant that simulated symptoms of diabetes, orthe justly celebrated armadillo, found many years ago to pinch-hitfor leprosy.AIDS is a hold-out.Humans' closest relatives are the subhuman primates, butchimpanzees and monkeys fail to cooperate as surrogates forstudying HIV infection and symptoms. Even if the virus succeeds inestablishing a beachhead in their blood, they simply don't succumbto the pitiless progression of symptoms _ collapse of immunity,onset of opportunistic infections and death.This lack of an adequate AIDS-modeling subhuman primate makeslife hard for researchers developing drugs to fight HIV infection, orvaccines to prevent it.Ten dog-faced baboons (Papio cynocephalus) at the University ofCalifornia, San Francisco, are billed by their inventors as "the firstprimate model for AIDS in which animals not only are infected withthe human AIDS virus, HIV, but also develop AIDS as a result."That's what virologist Susan Barnett told BioWorld Todayyesterday. She is first author of a paper in today's issue of Sciencetitled: "An AIDS-like condition induced in Baboons by HIV-2."Chiron Enlists New ModelsBarnett developed this baboon model over several years in thelaboratory of virologist Jay Levy at the University of California, SanFrancisco. He was one of the first scientists, a decade ago, to fingerHIV as the cause of AIDS.While continuing to pursue development of the baboon model inLevy's lab, Barnett recently moved to Chiron Corp. in nearbyEmeryville, as a visiting scientist in viral immunobiology. "We'rereally looking forward here at Chiron," she said, "to using this modelfor looking at vaccines and anti-viral therapies."When she first joined Levy's group in 1990, she recalled, "beforetrying to infect a primate with HIV, we tried incubating their cellswith HIV-1 and HIV-2 in the test tube. HIV-1 didn't do very well inculture, but HIV-2 proved able to replicate, infect the cells and growto reasonably high levels."She then examined the blood of the one baboon in the lab, which hadbeen inoculated with HIV-2 by a previous investigator there. "I sawthat as a result of this infection, the animal was losing its CD4+ Tcells, which is characteristic of an AIDS-like condition. This got meexcited."Can 10 Baboons Be Wrong?Six years and nine baboons later, repeated experiments with twoseparate West African strains of HIV-2 demonstrated to Levy and hisco-authors the validity of the infected primates as stand-ins forhuman AIDS victims.One baboon in particular, inoculated on Jan. 23, 1992 with 5,000median tissue-culture doses of an HIV-2 strain from the Ivory Coast,passed rapidly through the early and late stages of AIDS:Lymphadenopathy set in within two weeks; his CD4 cell countdeclined over 16 months, then plunged from 2,000 to only 200 cellsper cubic millimeter; he suffered the typical afflictions of the AIDSsyndrome _ cachexia and weight loss, severe anemia,thrombocytopenia, platelet abnormalities, skin lesions and antibiotic-defying ulcerative gingivitis. The HIV-2 multiplied rapidly in hisblood.As Barnett recalled, "His condition came to a point where weactually had to euthanize this animal. It was the only humane thingto do.""His internal and external tissues," she added, "were indeedreflective of an AIDS-like condition _ fibrotic tumors all over hisbody, lymphocytic interstitial pneumonia; the virus was in all thelymphoid and intestinal tissues, similar to the life-threateningsecondary illnesses that happen in AIDS."These lesions resembled the Kaposi's sarcoma and pneumonia sotypical of humans with late-stage HIV infection.Barnett attributes these and other pathological parallels to thesimilarity between the baboon and human immune responses, bothantibody and cell-mediated. "We've certainly seen that at Chiron,"she said, "testing our HIV vaccine, and looking for an immuneresponse."Of the remaining nine baboons, four received injections of the IvoryCoast HIV-2 strain, and are advancing through the same clinicalprogression as the sacrificed animal. Three others inoculated a yearlater with a different strain, from the Gambia, are just beginning toshow signs predictive of symptoms. One control baboon remainsuninfected and seronegative.Virus recovered from the inoculated animals' blood, Barnett said, "is40 times faster, and better, at infecting cultured cells than the originallab strains we used to inoculate our baboons."Now comes the recombinant phase of fine-tuning the AIDS animalmodel. At Chiron, Barnett is preparing to clone viral envelope genesequences from HIV-1 into the genomes of HIV-2. "With thesechimeric viruses," she explained, "we can actually test HIV-1vaccines in the model."Other researchers, she observed, have tried HIV-2 in baboons. "Theysaw some infection, but not the degree of infection that we see withour strains, which give disease rather rapidly. That's the beauty ofit."The university has applied for patents, she said, "covering thesestrains in the baboon as a model for AIDS," with herself and Levy asprincipal inventors."Baboons breed well in captivity," Barnett pointed out. "They arenot endangered species, and can be imported. Also, they arerelatively cheap, even compared to rhesus macaque monkeys," butshe added as an afterthought, "our newly announced AIDS modelmay jack up the price a little bit, something we're already seeing."(One animal supply center, queried by BioWorld, quoted the tag onan adult baboon, three to five years old, at $500 to $1,000.)Therion Biologics Corp., in Cambridge, Mass., is also developinglive AIDS vaccines, both attenuated and recombinant. That firm'spresident, Dennis Panicali, told BioWorld Today, "Any advance indeveloping an AIDS animal model would be of tremendous help tothe development of better vaccine strategies."Apprised of the baboon model described in today's Science, headded, "If the disease symptoms and progression mimic whathappens in humans, I think it should certainly be of great help."Barnett concluded, "What's important in our baboon model is thatthe whole course of disease just mirrors what's happening inhumans." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.