Perspectives On Medical Research
Volume 5, 1995
Aping Science
A Critical Analysis of Research at the Yerkes
Regional Primate Research Center
B. AIDS Research
In response to the AIDS epidemic, the federal government has generously
funded AIDS research. A large percentage of the allotted resources has
focused on animal models, especially nonhuman primate models. This is
unfortunate because nonhuman animals exposed to HIV exhibit very different
clinical features from human AIDS victims. In addition, most of these
models involve immunodeficiency viruses that differ considerably from
human immunodeficiency virus (HIV). While these nonhuman primate studies
are being conducted, many important questions regarding AIDS remain unanswered,
awaiting the funding needed for human clinical studies.
1. Simian Immunodeficiency Virus (SIV)
Yerkes researchers have infected nonhuman primates with several different SIV
viruses in an attempt to model HIV infection.1 Some strains of SIV
cause illness in certain monkeys, others do not. One commonly used SIV--SIVsmm--infects
sooty mangabey monkeys, but does not make them sick. This same strain, however,
infects other primate species, including rhesus monkeys, and causes an immunodeficiency
syndrome that shares some features with human AIDS.1 Human AIDS
is most commonly caused by HIV-1, and uncommonly by HIV-2. HIV-2 differs substantially
from HIV-l, causes a less aggressive immunodeficiency syndrome, and is responsible
for only a small fraction of human AIDS. SIVsmm closely resembles
HIV-2 and is only distantly related to HIV-l.2
Many Yerkes research projects have investigated factors explaining why some monkeys (rhesus and others) become diseased from SIVsmm, but sooty mangabey monkeys do not. For example, Patricia Fultz and co-workers infected monkeys of different species with SIVsmm and measured a wide range of antibody and humoral immune responses.3 Whether any of their findings meaningfully relate to human AIDS is highly speculative, since species differ in immune system function in countless subtle ways. Not surprisingly, they noted significant differences between monkey species. For example, healthy, asymptomatic mangabey monkeys infected with SIVsmm show both high plasma levels of virus and CD8 + lymphocytes. In contrast, it is difficult to isolate either virus or CD8 + lymphocytes from the plasma of asymptomatic macaque monkeys infected with either SIVsmm or a related virus, nonpathogemc for macaques, known as SIVmac.3 Given the similarities and differences between primate species, it is likely that some nonhuman primate responses to SIV have parallels to certain aspects of the human immune responses to HIV. However, there is no reason to expect any given finding in SIV-infected monkeys to correspond to HIV-infected humans, greatly undermining the SIV model's utility.
Another series of SIV studies at Yerkes involved SIVsmm transmission from mother rhesus monkeys to their young, which found that the likely route of virus transmission was breast-feeding.4 These data, and that of other investigators,5 indicate that transfer of SIV rarely occurs in utero, unlike human AIDS, where the fetus is often infected transplacentally. This research, therefore, cannot ascertain whether or not human AIDS can be spread by breast feeding. The investigators have claimed that their model will help "evaluate potential therapeutic regimens to prevent maternal-infant transmission," but, since the transmission routes differ, the data obtained pertain only to SIVsmm in rhesus monkeys, not humans.
A follow-up study attempted to determine whether characteristics differentiating HIV infection in human children from adults also differentiate SIV infections in infant rhesus monkeys from adults.6 Since only three infected rhesus infants were studied, it was not possible to draw any firm conclusions, but certain differences between pediatric HIV and infant SIV were striking. The authors noted that "clinical features which are unique or more common in pediatric AIDS include failure to thrive, lymphoid interstitial pneumonitis (LIP), and progressive neurologic disease due to primary HIV infection of the central nervous system (CNS)."6
Failure to thrive is also seen in SIV-infected monkey infants, but this only reflects their general debilitation and does not validate the animal model. Two out of three SIV-infected infants did have interstitial pneumonia, but neither had the classic pediatric AIDS presentation of lymphoplasmacytic infiltrates within alveolar septa. Children with HIV commonly have HIV-induced CNS infection, but only one SIV-infected infant had similar primary CNS infection. While cytomegalovirus (CMV) and progressive multifocal leukoencephalopathy (PML) are rarely seen opportunistic CNS infections in pediatric AIDS, one of three SIV-infected monkeys had CMV, and another had PML. Data regarding bacterial infections and anemia were too scant to draw any firm conclusions. In conclusion, some attributes in infant SIV seem to correspond to pediatric AIDS, but there are marked differences in clinical presentation and course. There is, therefore, no reason to expect that any new findings from studies of SIV-infected infant monkeys would enhance understanding of pediatric AIDS.
Even though SIV infections only remotely resemble human AIDS, Yerkes officials have insisted that their SIV laboratory findings directly relate to humans. They have stated:
In May of this year, a research team led by Dr. A. A. Ansari, Professor of Pathology and Laboratory Medicine at Emory, published a scientific paper which reported that current tests for Acquired Immune Deficiency Syndrome (AIDS) may not reveal all people who are infected with the virus that causes the disease.
The clinical study was prompted by findings from a Yerkes Center investigation of sooty mangabey monkeys, which are naturally infected with an AIDS-like virus. The animals' immune system seems to have adapted to the virus, providing the monkeys some immunological protection from disease. Dr. Ansari's immunological research with these animals has important implications for the prevention and treatment of AIDS in people.7
In fact, prior to this report, clinical investigators had already recognized that current tests for AIDS infection did not identify all HIV-infected people. In 1989 David Imagawa and co-workers had utilized the very sensitive polymerase chain reaction (PCR) test to identify HIV in cells from humans who had no antibody detectable with traditional tests.8 Some understanding of this phenomenon of low-to-zero antibody production was obtained in 1985, when clinical and in vitro findings indicated that the B-cells of some HIV-infected individuals are prevented from producing HIV-antibody by HIV itself and/or by the CD8-type T lymphocytes.9
With that hypothesis already existent, Yerkes researchers used pokeweed mitogen to stimulate antibody production from B-cells in vitro by growing B-cells from sooty mangabey monkeys that had been exposed to SIVsmm, but had not shown any antibody response to SIVsmm with standard tests, and then stimulating the B-cells to divide with pokeweed mitogen, removing CD8-cetls from the cell culture.10 They found that some B-cells from antibody-negative sooty mangabeys could express antibody to SIVsmm under these conditions, and they wrote, "These findings prompted us to conduct similar studies on a cohort of human patients."10 Although they did successfully study SIVsmm antibody production of cultured cells from sooty mangabeys, this research was neither necessary nor even prudent. In choosing to study monkey cells first (rather than available human cells), and in choosing to base clinical studies on monkey studies, the researchers risked advancing misleading conclusions resulting from differences in cell receptors and metabolism between humans and sooty mangabeys.
Yerkes officials have asserted that their studies of SIVsmm and other SIVs will shed light on how certain HIV-infected individuals are able to control the virus, a notion that is extraordinarily farfetched. All SIVs differ markedly from HIV-l. Further, monkey immunoregulatory response to SIVs differ vastly from human response to HIV-l and HIV-2. The question of how viruses such as SIVsmm adapt to their hosts over thousands of years is very different from the issue of human beings' ability to resist infection from a relatively recently introduced virus. Investigating how humans differ from each other in their response to HIV and other novel microorganisms would be much more relevant.
SIV research offers investigators nearly infinite research possibilities and opportunities, purportedly to address some of the many factors associated with HIV infection. For example, Yerkes researchers have studied the effects of opiate dependency on SIVsmm infection in rhesus monkeys. Noting that many human opiate abusers get AIDS, Robert Donahoe and colleagues reasoned, "it is logical to suspect that opiates might alter host susceptibility to productive infection with HIV- 1," but worried that "epidemiological assessments of heroin addiction are confounded by a great many uncontrollable variables." As often occurred in the past, they defended their monkey research on the dubious grounds that it is more "controlled." In rhesus monkeys infected with SIVsmm, they found that opiate-dependency did not increase AIDS-like symptoms. If anything, opiate dependency seemed to decrease signs of illness. To further complicate things, four of the six opiate dependent monkeys had been previously used in a five-year experiment involving effects of opiate-like drugs, and had experienced "various repeated incidences of withdrawal from opiates."11 It is possible that the immune responses to SIV in these monkeys was altered by prior invasive and stressful experimental manipulations, by conditioning factors, by undetected signs of debilitation, and/or by permanent opiate receptor change induced by chronic opiate dependence. Despite these difficulties, Donahoe and colleagues have defended this research in part on the grounds of "closeness of SIVsmm to HIV-l ," even though, as they themselves have acknowledged, the two viruses share only 40% genomic homology.11
Just as these animal models have had little role in understanding human AIDS infection, they have similarly not been very helpful in addressing AIDS therapeutics. As researcher Michael Wyand has noted:
[A]nimal models have played a small role in the development of drugs currently approved for use in humans or of drugs and vaccines about to enter into clinical trials. Candidate antivirals have been screened using in vitro systems and those with acceptable safety profiles have gone directly to humans with little supportive efficacy data from any in vivo system. This reasons for this are complex but include . . . the persistent view held by many that there is no predictive animal model for HIV infection in humans.12
2. Human Immunodeficiency Virus
Because chimpanzees are the only nonhuman animal whose healthy immune systems
can be infected with HIV-l, Yerkes researchers have studied HIV-l-infected
chimpanzees. Chimpanzees, however, do not develop any of the characteristic
clinical symptoms of AIDS, such as opportunistic infections or malignancies.5,13,14 Studies
at Yerkes and elsewhere have shown only that HIV-infected chimpanzees may develop
transient lymph node swelling.13,14a Furthermore, unlike human HIV
infection, chimpanzees do not show HIV infection of brain tissue or macrophages,
and HIV has not been found in chimpanzee cerebral spinal fluid or saliva.15 Finally,
unlike humans, chimpanzee immune systems mount little antibody-mediated or
cell-mediated responses to HIV-l.16 These differences may reflect,
in part, dissimilarities between human and chimpanzee immune system physiology,
such as their T4 to T8 lymphocyte ratios.17
Many HIV researchers have conceded that HI V-infected chimpanzees do not model human AIDS,18-20 and fundamental differences between humans and chimpanzees make the induction of human-like AIDS in chimpanzees unlikely. Despite the inherent limitations of using chimpanzees as models of HIV infection, Yerkes' Patricia Fultz still maintains that HIV-infected chimpanzees constitute useful models of "asymptomatic HIV carriers and vaccine efficacy,"13 arguing that further studies of HI V-resistance in chimpanzees may reveal ways of inducing HIV-resistance in humans. However, it is unreasonable to suggest that chimpanzee HIV-resistance models human AIDS resistance. In contrast, studies of people who have remained AIDS-free despite chronic HIV infection21-24 are more likely to reveal human mechanisms of HIV resistance and avoiding the onset of symptomatic AIDS.
Many researchers have advocated maintaining colonies of chimpanzees at Yerkes and elsewhere for testing potential vaccines against AIDS,13,25 despite the fact that chimpanzees differ from humans significantly in clinical and immunological features of HIV-1. Although chimpanzees do mount an antibody response after HIV-l exposure, its relevance to human immunologic response to HIV-l is not known.26 In any event, most potential AIDS vaccines pose little safety risks since they rely on genetically engineered fragments of the HIV's surface, not HIV's genetic material. Regardless of the actual value of vaccine tests on chimpanzees, pharmaceutical interests conduct them to satisfy FDA requirements, despite the FDA's having ignored certain chimpanzee tests of potential AIDS vaccines. For example, two vaccines used in clinical trials were initially found to be ineffective in chimpanzee studies,27 but the FDA was sufficiently skeptical of the significance of these findings to permit clinical trials of these vaccines.
In conclusion, the fundamental limitations of nonhuman primate models
of AIDS make them inappropriate choices of study to address remaining
critical questions. In order to effectively fight the epidemic, investigators
need to have greater understanding of the mechanisms of HIV transmission
in humans, the natural history of AIDS, and the human immunological response
to HIV. Thorough studies of humans exposed to HIV who develop and resist
HIV can address such issues. Although such studies are costly and time-consuming,
they represent the only means of obtaining reliable information
about AIDS.
1. McClure HM, Anderson DC, Ansari AA, Fultz PN, Klumpp SA, Schinazi RF. Nonhuman
primate models for evaluation of AIDS therapy. Annals of the New York Academy
of Sciences 1990;616:287-298.
2. Simon F, Matheron S. Tamalet C, et a!. Cellular and plasma viral load in patients infected with HIV-2. AIDS 1993;7:1411-1417.
3. Fultz PN, Stricker RB, McClure HM, Anderson DC, Switzer WM, Horaist C. Humoral response to SIV/SMM infection in macaque and mangabey monkeys. Journal of Acquired Immune Deficiency Syndromes 1990;3 :319-329.
4. McClure HM, Anderson DC, Fultz PN, et al Maternal transmission of SIVsmm in rhesus macaques. Journal of Medical Primatology 1991;20: 182-187.
5. Koch JA, Ruprecht RM. Animal models for anti-AIDS therapy. Antiviral Research 1992; 19:81-109.
6. Klumpp SA, Novembre FJ, Anderson DC, Simon MA, Ringler DJ, McClure HM. Clinical and pathological findings in infant rhesus macaques infected with SIVsmm by maternal transmission. Journal of Medical Primatology 1993;22: 169-176.
7. Yerkes Regional Primate Research Center, Public Affairs Division. Annual Report: The 60th Year, 1989-1990. Atlanta, 1990.
8. Imagawa DT, Lee MH, Wolinsky SM, et al. Human immuriodeficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. New England Journal of Medicine 1989;320: 1458-1462.
9. Nicholson JKA, McDougal JS, Jaffe HW, et al. Exposure to human T-lymphocyte virus type III/lymphadenopathy-associated virus and immunologic abnormalities in asymptomatic homosexual men. Annals of Internal Medicine 1985; 103:37-42.
10. Jehuda-Cohen T, Slade BA, Powell JD, et al. Polyclonal B-cell activation reveals antibodies against human immunodeficiency viruses type 1 (HIV-1) in HIV-l-seronegative individuals. Proceedings of the National Academy of Sciences of the United States 1990;87:3972-3976.
11. Donahoe RM, Byrd LD, McClure HM, et al. Consequences of opiate-dependency in a monkey model of AIDS, in Friedman H. Drugs of Abuse, Immunity, and AIDS. New York, Plenum Pr, 1993, pp 21-28.
12. Wyand MS. The use of SIV-infected rhesus monkeys for the precinical evaluation of AIDS drugs and vaccines. AIDS Research and Human Retroviruses 1992;8:349-356.
13. Fultz PN. Human immunodeficiency viris infection of chimpanzees: An animal model for asymptomatic HIV carriers and vaccine efficacy, in Koff W, Wong-Staal F, Kennedy R (eds). AIDS Research Reviews. New York, Marcel Dekker, 1991.
14. Fultz PN. Nonhuman primate models for AIDS. Clinical Infectious Diseases 1993; 17 (suppl 1) :S230-S235.
14a. As this document goes to press, Science (1995;270;223) reports that a chimpanzee has developed some symptoms of AIDS nine years after infection with HIV. This case has not yet been published, and the news report noted that researchers, including Yerkes’ Patricia Fultz, remain skeptical of chimpanzees’ usefulness for studies of HIV’s pathogenesis or for vaccine development.
15. Gardner MB, Luciw PA. Animal models of AIDS. FASEB Journal 1989;3:2593-2606.
16. Ferrari U, Ottinger J, Place C, Nigida SM Jr, Arthur LO, Weinhold Kr. The impact ofHIV-1 infection on phenotypic and functional parameters of cellular immunity in chimpanzees. AIDS Research and Human Retroviruses 1993 ;9:647-656.
17. Nara P, Hatch W, Kessler J, Kelliher J, Carter S. The biology of human immunodeficiency virus-IIIB infection in the chimpanzee: In vivo and in vitro correlations. Journal of Medical Primatology l989;35 :343-355.
18. Institute of Medicine. Mobilizing Against AIDS. Washington DC, National Academy Press, 1986.
19. Presidential Commission. Report of the Presidential Commission on the Human Immunodeficiency Virus Epidemic. Washington DC, US Government Printing Office, 1988, pp 39-47.
20. DeVita VT Jr, Hellman S, Rosenberg SA (eds). AIDS Etiology, Diagnosis, Treatment, and Prevention, 3rd Edition. Philadelphia, JR Lippincott, 1992.
21. Baltimore D. Lessons from people with nonprogressive HIV infection. New England Journal of Medicine 1994;332:259-260.
22. Cao Y, Qin L, Zhang L, Safrit I, Ho D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. New England Journal of Medicine 1994;332:201 -208.
23. Pantaleo G, Menzo S, Vaccarezza M, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. New England Journal of Medicine 1994;332:209-216.
24. Kirchhoff F, (Jreenough TC, Brettler DB, Sullivan JL, Desrosiers RC. Brief report: Absence of intact nef sequence in a long-term survivor with nonprogressive mv-i infection. New England Journal of Medicine 1994;332;228-232.
25. Van Akker, Balls M, Eichberg JW, et a!. Chimpanzees in AIDS research: A biomedical and bioethical perspective. Journal of Medical Primatology 1993;22:390-392.
26. Karzon DT, Bolognesi DP, Koff WC. Development of a vaccine for the prevention of AIDS, a critical appraisal. Vaccine 1992; 10:1039-1052.
27. Fauci AS, Fischinger PJ. The development of an AIDS vaccine: Progress and promise. Public Health Reports--Hyattsville 1988; 103:230-236.