Shortcomings of AIDS-Related Animal Experimentation

 

Stephen R. Kaufman, M.D.
Murry J. Cohen, M.D.
Steve Simmons

ANIMAL EXPERIMENTATION consumes much of the funding for research aimed at addressing the AIDS epidemic. The Medical Research Modernization Committee (MRMC) has identified fundamental scientific problems with animal experimentation in general1 and AIDS-related animal experimentation in particular.2 MRMC's booklet A Critical Look at Animal Experimentation explains animal experimentation's inherent flaws; offers political and social reasons for the continued support of animal experimentation by the government, medical centers, and the research establishment; and discusses relevant and reliable research methods.1
According to a 1996 Office of AIDS Research report that received considerable
media attention, projects "inappropriately" designated as AIDS research have received "a substantial proportion" of National Institutes of Health (NIH) funds earmarked for fighting AIDS.3 Grant-hungry researchers have also depleted AIDS research funds by performing highly dubious animal experiments. Since nonhuman animals do not get AIDS in nature, animal experimentation involves artificially inducing in nonhuman animals conditions that mimic AIDS in some ways but differ fundamentally in others.

Chimpanzees

Chimpanzees are the only nonhuman animals with a healthy immune system who can be infected with HIV-1, the cause of most cases of AIDS. Of approximately a hundred chimpanzees infected with HIV-1 over a ten year period, only two have become sick. The experimenters have thus far failed to inform the public how closely the disease states of these two chimpanzees resemble human AIDS. In any case, many AIDS researchers do acknowledge that chimpanzees are unsuitable for AIDS study because they rarely develop a disease after HIV infection, when they do it is only after a considerable length of time, and they belong to an endangered species.
In AIDS-related research, chimpanzees have been used mainly in vaccine studies that
can yield unreliable results. Unlike the human immune system, that of chimpanzees shows little antibody- or cell-mediated response to HIV-1.4 Further, chimpanzees differ from humans in their immune system ratios of T4 to T8 lymphocytes,5 a disparity that makes chimpanzees' immune response to HIV-1 infection virtually uninterpretable in human terms.6 As James Stott and Neil Almond warn, vaccine studies in chimpanzees may be totally inapplicable to humans: first, chimpanzees are too scarce for use in numbers sufficient to provide statistically significant results; second, AIDS-related experiments on chimpanzees employ laboratory-adapted strains of HIV-1 that differ from the naturally incurring [sic] virus; third, HIV-1's more limited replication in chimpanzees may make successful vaccination against the virus far easier in chimpanzees than in humans.7 Studies of people who have remained AIDS-free despite chronic HIV infection8 are far more likely to reveal means of enhancing human resistance to HIV than are experiments on chimpanzees.
Another factor that undermines the validity of AIDS-related research on
chimpanzees is the stress suffered by these sensitive, intelligent, and highly social animals from isolation, a barren laboratory environment, human handling, and inadequate living space. This laboratory-induced stress alters immune response and confounds the data.9
If we have learned anything from AIDS-related experimentation on chimpanzees,
it is that even subtle differences in immune system function can profoundly influence the course and response to treatment of infectious diseases.

Monkeys

The various simian immunodeficiency virus (SIV) strains do not appear to cause illness in their natural monkey hosts -- either in the laboratory or in nature. However, they may cause immunodeficiency diseases in other monkey species who are artificially infected in the laboratory, such as sooty mangabey SIV infecting rhesus monkeys. All strains of SIV differ markedly from HIV-1. Some SIV strains, however, resemble HIV-2,10 which causes a less aggressive immunodeficiency syndrome in humans than HIV-1 and is responsible for far fewer cases of AIDS.
In a recent review of AIDS-related animal experimentation,
Ann Lewis and Philip Johnson argue that SIV studies can elucidate HIV-1's mechanisms of infection.11 However, since SIV differs significantly from HIV-1, and infects monkeys rather than humans, the mechanisms of SIV and HIV-1 infection most probably differ substantially. Not surprisingly, our understanding of AIDS pathology and pathogenesis has derived from studies of human AIDS patients.12
Lewis and Johnson also claim that researchers can effectively use
SIV to test for anti-HIV-1 vaccines and therapies.11 However, they themselves note a critical problem with using SIV for AIDS vaccine research -- humans with AIDS produce antibodies against the V3 loop portion of a particular glycoprotein found on HIV's outer covering, but SIV-infected monkeys do not. (Monkeys infected with chimeric viruses composed of an SIV core and outer covering containing HIV-1 glycoproteins have shown only low levels of those viruses without disease.11) Also, SIV researcher Ronald Desrosiers acknowledges that SIV test results "vary greatly according to the strain of virus used for challenge."13 Since results from different SIV strains cannot be reliably extrapolated to one another, how can SIV findings be extrapolated to the substantially different HIV-1?
Michael Wyand concludes that AIDS-related animal experimentation has
"played a small role" in the development of anti-AIDS drugs and vaccines. Wyand observes that candidate antivirals have been initially screened in isolated proteins, cells, and tissues, and those judged safe based on these in vitro tests have proceeded directly to human testing with "little supportive efficacy data" from animal experimentation. One reason for animal experimentation's meager role in this process, Wyand notes, is a general lack of faith that any "animal model" has predictive value regarding HIV infection in humans.14

Cats

As Bennett and Hart note, feline immunodeficiency virus (FIV) is "more closely related" to non-primate lentiviruses (that infect horses, sheep and cows) than to HIV.15 Whereas HIV infection occurs through binding to the CD4 cell receptor, FIV infects by way of the CD9 cell receptor. While naturally acquired FIV infection causes many cats to become immunodeficient, FIV infection induced in the laboratory apparently does not.11 Most likely, FIV requires concurrent infections--those found in household cats but absent in the artificial laboratory environment--to cause immunodeficiency.

Mice

Mice with severe combined immunodeficiency (SCIDtm) lack functioning T and B lymphocytes (necessary for a functional immune system), and therefore their immune systems will not reject transplanted human immune cells, including those infected with HIV-1. Even with transplanted human immune cells, however, these SCIDtm mice do not have a standard human immune system, for such a system would identify the mouse's tissues as foreign, and attack and destroy them. SCIDtm mice with transplanted human immune cells infected with HIV-1 do not develop an AIDS-like disease from the virus, which shows only limited replication within their bodies.16,17 After seven years of experimentation with SCIDtm mice, Lewis and Johnson note, "The potential use of this model is not yet fully established."11

Conclusion

The 1996 report by the NIH Office of AIDS Research (OAR) recommends basic research to more fully identify AIDS pathogenesis, HIV gene-coded products and their functions, possible means of interrupting HIV's life cycle, humans' immune response to HIV infection, the mechanisms underlying opportunistic infections and malignancies, and the biological and behavioral aspects of HIV transmission.3 Unfortunately, the report endorses animal experimentation as one means of obtaining this relevant information, an endorsement that is unwarranted.
Considering the OAR's recommendations, human-based research is far
more likely than animal experimentation to produce findings about HIV and how it infects humans. To date, critical insights into AIDS disease mechanisms and therapy have derived exclusively from in-vitro and in-vivo studies of humans. In contrast, animals infected with various immunodeficiency viruses consistently fail to faithfully reproduce the human AIDS syndrome.
Regarding treatment of HIV infection, anti-AIDS drugs have been detected
in studies using cultured human tissue.18 Similarly, opportunistic infections and malignancies commonly found in AIDS patients differ from those afflicting animals with other immunodeficiency syndromes. Therefore, research on opportunistic diseases found in nonhuman animals cannot explain why many AIDS patients suffer from Pneumocystis pneumonia or Kaposi's sarcoma.
Regarding AIDS vaccine research, studies of nonhuman immunodeficiency
diseases are likely to remain unproductive. Researchers should instead study HIV-positive humans who remain free of AIDS. Finally, improved understanding of the behavioral aspects of AIDS transmission necessarily requires sociological and epidemiological research on humans.
In its extensive reviews of AIDS-related animal experiments, the MRMC has identified fundamental scientific flaws in all
experiments analyzed, and no evidence that these experiments have significantly advanced AIDS prevention or treatment. All species differ in their immune and other systems, and even subtle differences among them can result in major consequences. Humans are far more susceptible to HIV-1 than any other animal.
Stott and Almond comment that we can know which animal "model"
is best only "when we understand the pathogenesis of AIDS, and when we have vaccines and therapies that prevent it."7 This statement captures the fundamental pointlessness of animal experimentation; the validity of animal data can be measured only by comparison with already-obtained human data. The existence of the human data, however, renders the animal data superfluous. Despite its generous funding, AIDS-related animal experimentation has been unproductive, and there is no reason to believe it will prove to be any more valuable in the future.

 

1. A Critical Look at Animal Experimentation. New York, Medical Research Modernization Committee, 1995. See also MRMC's monograph series, Perspectives on Medical Research.

2. Committee on Animal Models in Biomedical Research. Aping Science: A Critical Analysis of Research at the Yerkes Regional Primate Research Center. New York, MRMC, 1995.

3. Report of the NIH AIDS Research Program Evaluation Working Group of the Office of AIDS Research Advisory Council. Washington, DC, Office of AIDS Research, March 13, 1996.

4. Ferrari G, Ottinger J, Place C, Nigida SM Jr, Arthur LO, Weinhold KJ. The impact of HIV-1 infection on phenotypic and functional parameters of cellular immunity in chimpanzees. AIDS Research and Human Retroviruses 1993;9:647-656.

5. Nara P, Hatch W, Kessler J, Kelliher J, Carter S. The biology of human immunodeficiency virus-1 IIIB infection in the chimpanzee: In vivo and in vitro correlations. Journal of Medical Primatology 1989;35:343-355.

6. Karzon DT, Bolognesi DP, Koff WC. Development of a vaccine for the prevention of AIDS, a critical appraisal. Vaccine 1992;10:1039-1052.

7. Stott J, Almond N. Assessing animal models of AIDS. Nature Medicine 1995;1:295-297.

8. Baltimore D. Lessons from people with nonprogressive HIV infection. New England Journal of Medicine 1994;332:259-260.

9. Barnard N, Hou S. Inherent stress: The tough life in lab routine. Lab Animal Sept 1988, pp 21-27.

10. Simon F, Matheron S, Tamalet C, et al. Cellular and plasma viral load in patients infected with HIV-2. AIDS 1993;7:1411-1417.

11. Lewis AD, Johnson PR. Developing animal models for AIDS research_progress and problems. Trends in Biotechnology 1995;13:142-150.

12. DeVita VT Jr, Hellman S, Rosenberg SA. AIDS Etiology, Diagnosis, Treatment, and Prevention, 3rd Edition. Philadelphia, JB Lippincott, 1992. Although the authors do not explicitly state that animal experimentation has failed to contribute to understanding or treatment of AIDS, their detailed review of AIDS-related research clearly demonstrates that human clinical investigation has played the primary role.

13. Desrosiers RC. Non-human primate models for AIDS vaccines. AIDS 1995;9(suppl A):S137-S141.

14. Wyand MS. The use of SIV-infected rhesus monkeys for the preclinical evaluation of AIDS drugs and vaccines. AIDS Research and Human Retroviruses 1992;8:349-356.

15. Bennett M, Hart CA. Feline immunodeficiency virus infection_a model for HIV and AIDS? Journal of Medical Microbiology 1995;42:233-236.

16. Gardner MB, Luciw PA. Animal models of AIDS. FASEB Journal 1989;3:2593-2602.

17. Klotman PE, Rappaport J, Ray P, et al. Transgenic models of HIV-1. AIDS 1995;9:313-324.

18. Mitsuya H, Broder S. Strategies for antiviral therapy in AIDS. Nature 1987;325:773-778.

 

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