[SOURCE: PROGRESS IN BIOMEDICAL RESEARCH 44(3): 10-13, 1994] BABOON MODEL FOR AIDS MAY BOOST TREATMENT EFFORTS A major problem in AIDS research has been the lack of an appropriate animal model. Now baboons may hold the key to future AIDS treatment and preventlon. In ground-breaking research involving baboons at Southwest Foundation for Biomedical Research, scientists have reported the first primate model for AIDS in which animals not only are infected with the human AIDS virus, HIV, but also develop AIDS as a result. AIDS is a disease that decimates the immune system and causes death. The study was conducted by a team of scientists led by Krishna K. Murthy, D.V.M., Ph.D., associate scientist in Southwest Foundation's Department of Virology and Immunology; Jay A. Levy, M.D., professor of medicine and research associate at the University of California at San Francisco Cancer Research Institute; Brian Herndier, M.D., Ph.D., assistant professor of pathology at the UCSF-affiliated San Francisco General Hospital; and Susan Barnett, Ph.D., who formerly worked in Dr. Levy's laboratory and now is with Chiron Corp., in Emeryville, Calif. They reported in the journal Science on Oct. 28 that 10 baboons (Papio cynocephalus), which have immune systems similar to those of humans, were infected with HIV-2, a form of the AIDS virus found primarily in West Africa. Like the more common HIV-1, HIV-2 infects humans and can cause fatal disease, although the development of full-blown AIDS with HIV-2 might be longer. Previous efforts to develop primate models for AIDS have focused on HIV-1 as the infectious agent. Chimpanzees and some monkeys--but not baboons -- have been successfully infected with HIV-1. These infections, however, have not led to persistent virus replication in the animals, nor to AIDS. The Foundation became a crossroad for the nation's leading AIDS researchers in 1984 when scientists were the first to establish the chimpanzee as an animal model of HIV-1 infection. Since then, research has been limited in the sense that chimpanzees are expensive and scarce. Moreover, studies with SIV (simian immunodeficiency virus) that causes AIDS-like disease in rhesus monkeys help but may not yield the same results as studies with a human immunodeficiency virus. HIV-2 has all the genes, structures, and infectious characteristics of HIV-1, although it is more similar genetically to SIV from the sooty mangabey monkey in the wild. This feature probably accounts for the ability of HIV-2, but not HIV-1, to infect baboons and cause AIDS, Dr. Levy said. There is evidence suggesting that the sooty mangabey was the potential zoonotic reservoir of the virus that became HIV-2, or crossed over into the human population. HIV-2 was discovered in 1985 in the West African country of Senegal. "The baboon model is a great resource for studying immune responses," said Dr. Murthy, who directs the primate virology laboratory at the Foundation, home to the world's largest baboon breeding colony, numbering 2,900. "We want to understand how a specific immune system cell, called an activated CD8 positive cell, prevents HIV infection from progressing to full-blown disease." Related studies in Dr. Murthy's laboratory indicate that although chimpanzees are susceptible to infection with HIV-1, they do not develop immunodeficiency or full-blown AIDS because activated CD8 cells block viral replication, and prevent dissemination of infection thereby preventing disease progression. The blocking effect is mediated by direct cell-to-cell contact between virus-infected CD4 cells and activated CD8 cells, and by the release of virus inhibitory factors from CD8 cells. Dr. Levy originally discovered the effect of activated CD8+ cells during studies of HlV-infected patients in San Francisco who survived infection without contracting AIDS for more than 10 years. Their long-term survival is a result of maintaining high levels of CD8+ cells with anti-HlV responses, he said. These white blood cells or lymphocytes make proteins important in regulating the immune response and fighting disease. The main target of HIV is the CD4+ Iymphocyte, which it infects and then kills. CD4+ cells, which also are important for regulating the immune response, and CD8+ cells are both immune system T cells, named for telltale markers on their surfaces. T cells comprise a major branch of the body's cellular armed forces and are mobilized by the body to attack cells infected with the virus. Mutation How HIV strains evolve or emerge in the host is not yet known. It has been suggested that a deadly strain present early in infection is either suppressed or eliminated by an active immune response but that a less virulent strain remains. Alternatively, the initial virus is not very pathogenic in the infected person, but, with increased replicative cycles resulting from reduced anti-HlV activity in the body, it mutates over time to a deadly strain resistant to the immune response. In research supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health for $300,000 over three years, Drs. Murthy and Levy plan to construct a chimeric molecule or hybrid of HIV-1/HIV-2, which would trick the baboon's immune system into incorporatind DNA from HIV-1 into its cells. Thus, it would be possible also to test drugs against the more prevalent HIV-1. Baboons were considered as possible animal models after the AIDS epidemic began in 1981, but when they could not be infected with HIV-1, researchers abandoned the idea. The scientists reported in Science on five baboons injected intravenously with a single strain of HIV-2 from the Ivory Coast. The first animal was injected in September 1988 and within a few weeks developed antibodies against the AIDS virus, a sign of infection. Within 18 months, the animal's CD4+ cell counts began to decline, a hallmark of HIV disease progression--and the baboon continues to test positive for HIV after six years. Four other animals, each injected with the same HIV-2 UC2 strain in January 1992, have developed enlarged Iymph nodes, a symptom of HIV infection in people. Antibodies against HIV were detected within four to six weeks and remain at high levels. In addition, more than two years later, three of these four animals exhibit immune changes typical of HIV infection progressing to AIDS, including a marked decline in the number of CD4+ cells in the blood. One animal developed life-threatening secondary illnesses commonly seen in AIDS. These conditions included Iymphocytic interstitial pneumonia, which often afflicts children with AIDS; the growth of fibrous lesions below the skin resembling those observed in Kaposi's sarcoma, a cancer commonly found in homosexual men with AIDS; and severe weight loss similar to the wasting that occurs in human AIDS patients. The lymph nodes also deteriorated, accompanied by a rapid increase in the amount of HIV virus circulating in the blood, events that also occur during the last stages of AIDS in humans. A second animal is losing lymph node function and developing fibrous tumors, and appears to be progressing towards AIDS in a similar manner. In January 1993, three additional baboons were infected with a different strain of HIV-2, UC12 from Gambia, and they remain HIV-positive today. The potential of baboons to be infected with multiple strains of HIV holds promise for testing vaccines, which must protect against a range of HIV strains, Dr. Levy said. Recognizing that HIV genetically changes and evolves naturally within humans into forms that are more infectious and which can lead more quickly to full-blown disease, Dr. Levy believes that the same process can occur in baboons. To wit: the scientists have found that the virus recovered from baboons with long-term infection grows more rapidly in the laboratory and to higher levels than the strain injected originally. Dr. Murthy and his colleagues now are serially injecting baboons with HIV-2 recovered from baboons with AIDS. The scientists report that 32 weeks after injection into two baboons, the virus was persistently replicating in the blood of both animals, showing substantial infection. Although only a few dozen cases of HIV-2 have been confirmed in the United States, HIV-2 is spreading worldwide, especially in Africa and India. The similarities in the baboon and human immune responses should provide an opportunity to improve our understanding of how AIDS is caused in humans through studies with baboons, Dr. Levy said. The research breakthrough involving HIV-2 was first announced by Dr. Levy to researchers attending the Tenth International Conference on AIDS in Yokohama, Japan, in August. He was one of the first scientists to identify HIV as the cause of AIDS in early 1984.