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March 2000
Effective or Not?: Animal Models of AIDS

By Ray Greek and Jean Swingle Greek

 

 

AIDS (acquired immunodeficiency syndrome) and the virus that causes it, HIV (human immunodeficiency virus), has reawakened the medical community to the dangers of infectious diseases. With the invention of antibiotics and subsequent containment of bacterial infections, the medical community had hoped that killer epidemics were a thing of the past. Then came AIDS.

Caused by a virus, AIDS is not vanquished by antibiotics. Viral diseases are not easily cured, but may be prevented, hence the search for an AIDS vaccine. As is often the case, researchers turned to animal models in search of an answer to the "AIDS vaccine" question. They should have known better.

For decades scientists have known that animal models of human viral diseases simply are not predictive for humans. For example, the mouse model of influenza is a poor replica of the human illness. The classic signs of influenza in humans—fever and nasal discharge—do not occur in mice. The 1999 Handbook of Animal Models of Infection states, "The mouse model is somewhat unrelated to the more typical influenza virus infection seen in humans." The Handbook continues: "Up to this very day, all infectious diseases affecting humans are far from having appropriate animal models and, even in those cases where such infections are possible, the symptoms observed in animals and the course of the disease are often very different from those encountered in humans. One must be aware of the many limitations of using laboratory animals to model infectious processes." Even Albert Sabin, inventor of the polio vaccine, stated before U.S. Congress that ‘the polio vaccine was delayed because of animal models.’

HIV is a much more complicated virus than most, but still researchers pursue treatments and vaccines for AIDS using animal models Even though some of the vested interests knew there was a problem. Researchers have stated in Science, that "no animal models faithfully reproduce human immunodeficiency virus type 1 (HIV-1) infection and disease in humans." And, "a molecular clone of the prototype SAIDS virus (the monkey version of AIDS)…has no notable similarity in either genetic organization or sequence to the human AIDS retrovirus." (emphasis added) And, "there is a big leap from monkeys to humans: For starters, HIV-1, the main AIDS virus that infects humans, differs significantly from SIV."

Much time, money and personnel have gone into studying animal models in order to develop a vaccine, but with no success. Dr. Mark Feinberg stated in the Atlanta Journal Constitution, "What good does it do you to test something [a vaccine] in a monkey? You find five or six years from now that it works in the monkey, and then you test it in humans and you realize that humans behave totally differently from monkeys, so you’ve wasted five years."

More and more scientists are acknowledging the obvious: animal models of AIDS are misleading. Steven Bende, research coordinator at the National Institute of Allergy and Infectious Disease, stated in the August 1999 issue of The Scientist, "The chimpanzee model doesn’t get a lot of support in the scientific community." He emphasized that the lack of scientific merit and no formal government policy has dictated that the chimpanzee model is not useful. Dr. Bende also underplayed the usefulness of the monkey model saying, "SIV in monkeys is not the same as HIV in humans."

In the same issue of The Scientist, Thomas Insel, former Director of the Yerkes Regional Primate Center, stated, "I just don’t see much coming out of the chimp work that has convinced us that that is a particularly useful model. [An animal model] that takes 12 to 14 years to develop doesn’t sound to me to be ideal." Insel believes that the two decades of AIDS research in chimpanzees has done little to ease human suffering: "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."

Why did all of these scientists say that the nonhuman primate models of AIDS are inadequate? There are many reasons, but it is sufficient to say here that the immune system of humans is unique. So are those of rhesus monkeys and chimpanzees. These are three different species with three different immune systems. For example: in chimpanzees, HIV does not reproduce well. It does in humans. Chimpanzees have HIV only in their red blood cells, while humans also have the virus in plasma. In spite of the fact that 98 percent of our genetic make-up is identical to that of chimpanzees, they do not come down with AIDS-like symptoms and they do not die as a result of HIV infection.

Monkey models do no better. The viruses human contract—HIV-1 and HIV-2—are very different from simian versions. HIV-1 shares only 40 percent homology with the other viruses. HIV-2 and SIV share 75 percent homology. That is a very significant difference.

The next example, however should serve as the most important illustration of why animal models of AIDS are ineffective. In order to penetrate the white blood cell, HIV must bind to two receptors. Think of it as unlocking two locks. SIV enters the cells of rhesus monkeys by binding to the CCR5 receptor (unlocking the CCR5 lock) without binding to the CD4 receptor (without unlocking the CD4 lock). In humans, HIV must bind/unlock both CCR5 and CD4 receptors/locks. Although this is only single amino acid difference between humans and monkeys in the CCR5 terminus is responsible for the difference in binding, it is a huge difference. To give some idea of the importance of a single amino acid difference, it is a single amino acid difference that is responsible for the diseases sickle cell anemia and cystic fibrosis. Very small differences on the cellular level between species, even species as closely related as humans and nonhuman primates, make for huge differences in disease response and treatment.

This unlocking mechanism is important for many reasons, one being that if we can glue one of the receptors/locks shut then HIV cannot enter the cell and human will be resistant to AIDS. For years, based on the monkey model drug companies and researchers only looked at gluing the one lock closed. They totally ignored the other thinking it irrelevant to HIV penetration.

Those who advocate for the use of primates in HIV/AIDS research continue to tout the case of a chimpanzee in Atlanta, Georgia named Jerom. They claim Jerom was infected with HIV and came down with AIDS. But a closer examination reveals some discrepancies. The virus used to infect Jerom was different from the HIV virus that normally causes AIDS in humans. When HIV infects humans for the first time it binds to the CCR5 receptor. Then it develops a preference for the CXCR-4 receptor. (It does this in addition to binding to the CD4 receptor.) The virus used to infect Jerom relied on the CXCR-4 receptor from the outset, and this was not the only difference According to an article in Science, after the virus was given to Jerom, it was given to other chimpanzees, causing their white blood cell counts to drop; but in contrast to Jerom, they did not exhibit signs of AIDS. Jonathan Allan stated in the same issue of Science, "thus they [the chimpanzees] do not mimic the initial infection in humans."

We derive our knowledge of HIV and AIDS from the same place all of our medical knowledge has come from: human based research involving research with human tissues and clinical research, and the knowledge that we will need for a vaccine will come from the same channels. It was this type of research that led Dr. David Ho to conclude that we should treat HIV positive patients early and aggressively with a multiple drug regime. The British Medical Journal stated, "Ho’s remarkable success, derived from clinical observation of patients is a classic example of what can happen when physicians actually try to learn about disease from humans."

Other human-based research modalities have also contributed: autopsies, in vitro research on human tissue from HIV positive patients, epidemiology, computer and mathematical modeling and the study of genetics. These modalities allowed us to determine how HIV was transmitted, the structure of HIV, how HIV gets inside the cell, which genes are predisposed to AIDS and which ones protect HIV POSITIVE patients from progressing to AIDS. Human-based research revealed that unlike the animal models, the virus in humans reproduces rapidly and therefore physicians needed to start treatment very soon after the patient becomes HIV POSITIVE. These modalities also gave us the drugs we currently use to treat AIDS and the ones we give to pregnant mothers to prevent their babies from being born with an incurable disease.

Computer models of HIV and AIDS have revolutionized AIDS drug design. Computer-designed nonnucleoside analogs have been shown to inhibit drug-resistant HIV. The computer model takes into account structural changes and residue characteristics resulting from mutations associated with clinical resistance to nonnucleoside inhibitors. Dr. Faith Uckun stated in Bioorganic & Medical Chemistry Letters, "We can predict how the AIDS virus will react to new agents that we develop that with the computer model...we now have the opportunity to rationally design very effective drugs against the multidrug-resistant AIDS virus."

In light of this evidence it is clear that animal models of human disease have never been predictive or effective. Today, they are stealing money from areas of research that hold promise for a vaccine to prevent AIDS.

Ray Greek is a physician who specializes in anesthesiology. He has performed experiments on animals and research with humans. Jean Swingle Greek is a veterinary dermatologist. She also teaches and does research at the University of Missouri College of Veterinary Medicine. She has performed experiments on animals. They now advocate against vivisection, and are co-authors of a book on the fallacy of using animals to study human disease, Sacred Cows and Golden Geese (Continuum, spring of 2000).

 


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