Cats, AIDS, and Grantsmanship

By John McArdle, Ph.D.

For nearly two decades, the worldwide biomedical research industry has chosen to repeat a failed approach to human health problems in an attempt to justify new expenditures of billions of dollars and millions of animal lives in unnecessary experiments. Animal-based experimentation periodically needs new diseases or health threats to scare the public, Congress, media, and sources of funding into providing money and to defend their continued reliance on out-dated, non-human in vivo research models. They have replaced the previously failed ‘war on cancer’ with an equally questionable ‘war on AIDS.’ Investigators continue to ‘discover’ that their animal-based projects are suddenly relevant to AIDS. Although cats were rarely drafted into the fight against cancer, their ranks in the AIDS battles are increasing dramatically because of a supposedly AIDS-like pair of feline viral diseases.

When the ‘war on cancer’ was initially announced, biomedical researchers immediately called press conferences to announce dubious or entirely fictional advances in treating human cancer, rewriting their grant proposals to make them more relevant to cancer research (even if unrelated to the disease) and making every conceivable effort to get a piece of the hundreds of millions of new dollars available to support such efforts. There were standing jokes at many research facilities (including the institution where I worked) about finding ways to work the word cancer into research proposals—a classic example of grantsmanship at work. What did the American public gain from all of those manipulations? Scores of laboratories were equipped and funded, careers were made, salaries guaranteed, buildings erected, and millions of animal lives were lost.

There is ample documentation that this ‘war on cancer’ was lost. Except for a few rare examples, death rates were no better after a decade of combat, or had perhaps become worse. In large part ,this was attributed to an overemphasis on animal-based research protocols and an underemphasis on the use of appropriate alternatives and scant attention to prevention. A similar scenario awaits the retrospective analysis of animal-based models of AIDS.

Cats and AIDS

A fundamental and often ignored question in biomedical research is how low will scientists and their sources of funding set the bar for biologically justifiable animal models of human diseases. For AIDS research, the bar appears to be lying on the ground.

The top of the list for validation criteria for animal models should include the same symptoms, causes, biological mechanisms, and responses to treatment as the human disease. This seldom happens, with the supposedly AIDS-like feline viral diseases being no exception. Primary criteria seem more related to logistical and practical considerations, such that "cats fulfill desired handling, housing, and availability criteria for effective AIDS models." They are relatively inexpensive (in comparison to non-human primates). There is a large population of naturally infected cats and abundant supplies of SPF (specific-pathogen-free) animals from commercial breeders to provide for endless parametric tinkering of potential co-factors and treatment options. Cats are described as a more reliable and easier "drug delivery system."

Feline leukemia virus (FeLV) was first identified by William Jarrett at the University of Glasgow in Scotland in 1964. It is a type C retrovirus, lacking many of the regulatory and accessory genes found in the human immunodeficiency virus (HIV) that produces AIDS. Endogenous FeLV-like viral fragments have been identified in domestic cats and wild species of Mediterranean origin but not in felids from sub-Saharan Africa, Asia, or the Americas. A related sequence found in rats may represent the original origin of the disease.

Unlike HIV, FeLV is primarily transmitted horizontally (to other cats) via saliva. Infection can result in no disease (in a high percentage of cases), anemias, immunosuppression, kidney disease, lymphomas, and opportunistic infections—but rarely leukemia. Due to significant differences (see below), less emphasis has been placed on using this model.

Feline immunodeficiency virus (FIV) was first identified in 1986 from FeLV negative, immunodeficient animals in a large cat breeding facility in Petaluma, California. Other versions of this virus are found in domestic cats worldwide and such wild species as African lions, tigers, panthers, and bobcats. As with the non-human primate SIV viruses, natural FIV infections in wild cat species are widespread but do not kill the animals. All of the available evidence suggests FIV has been present in cats for a very long time, predating their domestication.

For house cats, FIV is most prevalent in older, free-ranging males due to restricted transmission abilities. Like FeLV, the primary route of infection is by exposure to saliva. Unlike FeLV, FIV cannot be effectively transmitted horizontally or vertically (to offspring) within cat populations without the presence of co-factors such as FeLV. This latter characteristic has produced some bizarre research proposals, such as concurrent exposure to drugs of abuse—not a generally recognized problem in companion cats. FIV infected cats are characterized by such general clinical signs as dullness, swollen lymph nodes, anorexia, weight loss, and infections.

Problems with Feline AIDS Models

In general, cats are not suitable for any type of drug studies (clinical or abuse) other than those specifically tailored to the medical needs of the animals themselves. With their special adaptations for protein metabolism, cats have lost many of the biotransformation mechanisms that characterize humans in particular and other laboratory animals in general. Due to unique species-specific responses, cats are especially unsuitable as models of human substance abuse. These qualities should have ruled out felines as animal models regardless of the other problems associated with feline retroviral diseases.

According to animal-based AIDS researchers Ronald Desrosier and Norman Letvin, "numerous differences" exist between FeLV and HIV, as well as the diseases they induce. These include FeLV's lack of the high degree of variability that typifies HIV isolates, the broad range of cellular targets seen with FeLV, failure to form a cytoplasmic syncytium, the active role in cats of neutralizing antibodies in controlling viral replication; primary horizontal transmission via saliva (HIV utilizes sexual contact and blood), and significant differences between natural and laboratory-induced FeLV infections.

Clinically, only 30 percent of exposed cats progress to the full-blown disease state, with the majority recovering from natural exposure. This is not the situation with human exposure to HIV. FeLV myeloid tropism also leads to a variety of disease expressions not commonly associated with AIDS.

FIV exposure presents a similar picture. It is difficult to produce infections in the laboratory without the use of co-factors such as concurrent FeLV exposure. This creates a serious dilemma for data interpretation, since FeLV by itself has the ability to produce significant immunosuppression.

As originally described, "different FIV isolates appear to show less variability within single FIV-infected cats than HIV-1 does in individual humans." FIV appears to utilize several cellular receptors not in common with HIV. FIV is transmitted via saliva but with more difficulty than characteristic of FeLV. The virus infects a wider range of cell types than HIV and is genetically distinct from other types of lentiviruses, including HIV and its non-human primate surrogate SIV.

Clinical observations on FIV infected cats mimic those associated with HIV in humans. There are, however, significant differences between the two. Mortalities in laboratory FIV experiments are characterized by such a wide range of pathologies that no common link to only FIV is generally apparent. In contrast to HIV, virus-specific protection against FIV is possible in cats, and a larger percentage of infected individuals survive. FIV researchers have described six distinct clinical phases (HIV has only five), with those cats surviving stage five developing medical conditions not typically seen with AIDS.

Spawn of FeLV, FIV, and HIV

Like any good Socratic argument, if one accepts the initial assumptions, everything that follows (no matter how irrelevant or bizarre) appears to be valid and appropriate. This is the case with feline-AIDS models. A nearly unlimited variety of research protocols, examining every possible combination and permutation of parameters (i.e., virology, clinical, biochemical, behavioral, etc.) have been and are being proposed for feline models of human HIV infection. Such protocol tinkering often involves completely unrelated species or test substances to which cats respond differently than humans.

In Mexico City, a research team examined the effects of HIV and FIV viruses on learning, memory, sleep-wake cycles, and locomotor behavior in rats as a putative model for HIV associated dementia in human patients. Such mix and match shuffling of respective viral parts (components) is common. At Cornell University Medical College, investigators are examining the use of modified FIV viruses for gene therapy. In this case, non-human primates are utilized as surrogates for human patients. In bizarre attempts to replicate aspects of human sexual behavior in cats, some laboratories are creating routes of FIV exposure that would never be found in nature.

Perhaps the most biologically and scientifically unjustifiable spin-offs of feline-AIDS research are the various protocols designed to transform FIV infected cats into surrogates for human junkies. A series of projects at Scripps Institute looked at the effects of methamphetamine exposure on FIV positive cats because a significant number of human AIDS patients either acquired the virus through the use of that drug or during the course of their disease. At the Vaccine Research Institute in San Diego, researchers are developing a FIV model for multiple acute morphine exposures. Specifically, the cats supposedly replicate the conditions associated with human weekend opiate abusers (i.e., non-dependent, non-addicted, non-tolerant people). Not surprisingly, such morphine exposure in cats (who react differently than humans to this drug) did not increase the severity of early viral infection and, in fact, delayed or moderated the progression of the disease—a finding inconsistent with human AIDS clinical experience.

Dr. Michael Podell, formerly of Ohio State University, conducted FIV based studies on a feline model of AIDS induced dementia in humans and, most recently, how substance abuse may speed up the progression of HIV. Podell has become a poster child for those individuals and organizations dedicated to promoting animal experimentation regardless of its biological or medical relevance. When Podell announced termination of his cat research program, most likely in response to a lack of institutional and professional support, his defenders played the terrorist and anti-science cards to demonize legitimate critics of his work. Podell, however, provides one of the best-documented examples of feline AIDS grantsmanship at work.

As shown above, cats do not get HIV, and feline immunodeficiency virus (FIV) is only distantly related to human HIV. Cats also do not naturally ingest narcotics, nor do they respond like humans as a result of induced exposure. Podell's research projects are classic examples of fudging grant requests to make them relevant to the currently popular source of funding. Twenty years ago, he would likely have written the same proposal but made it relevant to the progression of cancer. His research is more about manipulating the NIH grant system rather than any concern about human drug abuse or HIV patients. If he were serious about these clinical issues, his questions could have been formulated in such a way that human epidemiological research would provide the answers.

All scientists who receive NIH funds are required by federal law to show that they considered non-animal alternatives before they began their research. Examination of the protocol approval document Podell submitted to the Ohio State University Institutional Animal Care and Use Committee identified obvious and apparently either unrecognized or ignored problems. And it is clear that Podell made no serious effort to consider alternatives. He examined the wrong databases, used the wrong key words, structured his ‘search’ for alternatives to retrieve only references to exactly the same type of work he was doing, completely ignored databases with possible information relevant to refinement and reduction, and selected key words designed to find only animal-based studies. The project also involved excessively large sample sizes (i.e., 120 cats in six experimental groups).

It is particularly confusing that his criteria for early removal of cats from the experiments are related to similarities he claims exist between HIV and FIV. All of the animals removed from the study and killed suffered and died for nothing—not even to produce fictitious data. The protocol description also suggests that many of the cats would experience intense physical distress possibly for as long as two years.

Conclusions

Although research on FeLV and FIV could be justified to produce vaccines that protected domestic cats from infection or clinical advancement of the disease, the biomedical research industry chose a different path. They repeated the same historical pattern of disease focus, questionably related animal models, available research dollars, and career advancement. Critical examination of the genuine (versus public relations exercise) progress in AIDS research and understanding suggests little or no legitimate need for these animal models. As a consequence, the cost in animal suffering, questionable projects, wasted research dollars, and a continued failure to protect the public's health and safety for the ‘war on AIDS’ will be considerably greater than the previously failed animal research-based ‘war on cancer.’

McArdle, John, Ph.D. (Winter 2003). AV Magazine. Pages 14-17.

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