Letters

From the April 1995 issue

(Page 2 of 4)

4) There are reasons other than epidemiologic ones to think that HIV causes AIDS. Despite denial by Thomas et al., there are animal models for HIV/AIDS of similar quality to animal models for most diseases. Since viruses are generally more species specific in action than drugs, lab-animal virus infection models must usually use animal viruses. Fortunately, HIV is but one member of a family of related nine-gene slow-acting brain-infecting mammalian retroviruses ("lentiviruses") which are very similar to each other in structure, genetics, and appearance. Several of these also (just coincidentally) cause animal immunodeficiency syndromes as close to human AIDS as it is realistic for an animal to exhibit. The feline immunodeficiency virus (FIV) and simian immunodeficiency virus (SIV) cause deadly immunodeficiency diseases in domestic cats and Asian monkeys, respectively.

The destruction of immune systems by FIV and SIV models the human immune destruction seen in AIDS better than that produced by any other known immunosuppressant treatment in animals. Cats and Asian monkeys infected with FIV or SIV preferentially lose CD4 lymphocytes, and are afflicted with viral brain lesions, wasting, lymphadenopathy, lymphomas, and infections. Monkeys develop CMV viral retinitis, Pneumocystis pneumonia, M. Avium disease, disseminated candida, and cryptosporidial intestinal disease. All these are opportunistic infections not common in monkeys, and almost unknown in young humans before AIDS (they are very common in AIDS). Most significantly, all these pathologies happen in monkeys due to levels of lentiviral activity much like those in HIV-infected humans, so there is nothing about human HIV infection that contradicts the possibility of a similar virus-caused immune destruction mechanism operating in humans.

Ignoring such similarities, Thomas et al. deny the animal models of AIDS by focusing on latency period. They incredibly call latency studies "tall tales," though even the classic original slow virus findings in Icelandic sheep have by now been well confirmed, with up to eight-year latencies being demonstrated for experimental infections. Duesberg denies the existence of any latent viral disease syndrome following host serum immunity, thus denying the findings of dozens of research groups on slow retrovirus infection in sheep, goats, horses, cows, cats, and monkeys (Duesberg, disbelieving in slow viruses, insultingly calls all these scientists "slow virologists"). Thomas et al., following Duesberg's idiosyncratic and unaccepted view in the matter, go so far as to proclaim that in monkeys "SIV disease follows the primary infection closely"--a generalization contradicted by many independent reports. While experimental SIV disease in monkeys may cause simian AIDS rather immediately (just as HIV does occasionally in humans), SIV may also cause immune-failure death up to three years after initial infection and after a previous good immune response. Deaths in closed colonies of monkeys due to SIV infection (and also in the face of good immune response) have been recorded after latencies of up to seven years. In FIV in cats, another slow virus model, the latency for immune failure, lymphoma, and death after experimental infection is 18-24 months and may be as long as three years. Again it occurs long after the apparent full recovery with good immune response that follows primary FIV infection in cats.

5) Can it be coincidence that HIV, which is the closest human relative to the simian immune-system-destroying retrovirus SIV, is the virus most commonly found throughout every class of AIDS patient? It is true that the more familiar strain of HIV, called HIV-1, infects but does not cause severe illness in monkeys (just as yellow fever does not). However, preliminary reports from several labs now show that HIV-2, a related retro-virus isolated from many AIDS patients in West Africa, does indeed cause death from immunodeficiency when injected into Asian monkeys. It would be a stupendous coincidence if HIV-2 causes immune failure and death in both humans and animals, while at the same time HIV-1, the related strain found in U.S. serum-exposed patients who are severely immunodeficient, is a harmless bystander--yet this is the suggestion of the skeptics. May we now hear from them an admission of probability that at least HIV-2 is a likely cause of some AIDS cases, if not HIV-1?

I suspect no such admission will be forthcoming, when Thomas et al. assert that lab animals "tend to have weakened immune systems," a statement perhaps meant to invalidate any lab-animal experiment showing immune suppression results which threatens the authors' hypotheses. In domestic cats, FIV was first isolated from cats in a household with dying pets, and it also causes disease in feral animals, so it is hardly an artifact of the laboratory setting. Still, if we can-
not trust laboratory retrovirus infection data, what are we left with? The authors dismiss epidemiological results they don't like as mere "correlation." Skeptics have thus carefully set a task for science which may be impossible, for it is always possible to find faults and differences in any laboratory animal model and always possible to find something not carefully enough controlled in any epidemiologic study.

6) HIV/AIDS skeptics say that what they want most is new definition of AIDS not involving HIV, so let us here suggest one for heuristic purposes. Our task is to decide what disease entity it is we're trying to nail down with a definition, and why. Two characteristics stand out: 1) The new disease which emerged from ob-scurely low levels in 1981 in the United States was acquired, meaning that it occurred epidemically in previously well people who had had intimate contact with body fluids of others who were to develop the same syndrome, and 2) this new plague was a severe immunodeficiency which was invariably fatal.

How do we gauge "severe" (life-threatening) immune problems, for purposes of definition? We can crudely quantify immune function and project what degrees of loss are dangerous and predictive of death with a simple count of the CD4 blood lymphocytes. An immunologically healthy person's CD4 count is perhaps 1,000. Less than 200 is critically low and can be termed "immune failure," because this is the approximate number below which opportunistic-infection fatalities are increasingly seen. Most AIDS patients actually travel far beyond this boundary: Today, fully 85 percent of AIDS patients survive long enough to see their CD4 counts fall below 50, with some going all the way to a count of zero before death. It is these patients with life-threatening immunological destruction and very poor prognosis who constitute the core of what most people mean by "AIDS."

If we define "AIDS," then, as otherwise unexplained immune failure in body-fluid-exposed people, we will capture in our definition at some point during life almost everyone who ultimately dies as a result of this syndrome, and we will diagnose almost no one who has more than several years life expectancy. Thus, our definition will do the main job. Moreover, using this definition, we find that the fraction of "AIDS" patients who just happen to have HIV is essentially 100 percent, so we do not have to deal with "HIV-negative AIDS." Why, then, don't critics who don't want to talk about HIV tests use this stringent HIV-free definition and be done with it?

The answer, possibly, is that it would leave them with nothing to complain about. Critics want the existence of HIV-negative AIDS, and in order for this phenomenon, so dear to skeptics, to exist, "AIDS" must be defined by much less- strict criteria than we just proposed. Critics are always happy to do just that. As example, consider the 90 or so HIV-negative people in the United States who have been identified so far with CD4 counts less than 300 (not the critical 200 for AIDS, but approaching it). It was pointed out in REASON by the letter from CDC scientists (Dec.) that these people with "ICL" are epidemiologically different from AIDS sufferers, a statement which Thomas et al. dismiss as meaning "apparently that they are not linked to HIV." Not so. The problem is that ICL sufferers have no evidence of an acquired problem--they are not only HIV-negative but they are also not gay men, drug users, hemophiliacs, or transfusion recipients either, so their existence is as detrimental to the REASON authors' alternate AIDS-causation case as it is to the case for HIV.

There are similar problems with modifying the entire CDC AIDS definition by simply removing any mention of HIV--also a favorite ploy of critics. The problem is that HIV status in the CDC definitions is not there just to make skeptics unhappy and uphold the HIV theory; it also has a prognostic value for people with moderate immune problems and disease. If HIV-negative, such people may recover or at least get no worse over the long term, but if HIV-positive they invariably become more immunocompromised, and die within a few years.

Although Thomas et al. do not pause overlong to wonder why HIV is the only virus infection of moderately immunocompromised people that has such prognostic value for future total immune failure, they do admit the association. Certainly, then, they should understand why it is unfair to remove a criterion which is doing prognostic work in a disease definition, then make much of the fact that the resulting mutilated set of criteria no longer does what it was designed to do.
It is this kind of thinking which allows critics to suggest that many HIV-negative people in the 1993 San Francisco study really had "undiagnosed AIDS" because they developed some of the milder "AIDS-defining diseases." Again, however, no one ever suggested that all diseases that are AIDS-associated secondary diseases are by themselves prognostic of future immune failure and death. The point of the San Francisco study was not to find which group(s) has any opportunistic-type diseases, but rather to see which group(s) inexorably suffers progressive immune function loss and high mortality, which is closer to what we all recognize as AIDS.

It is best to leave secondary diseases out of the definition of AIDS entirely if HIV status is also not included, yet critics persist in doing this, and may even go further. Duesberg has gone so far as to count many clinically healthy people with only mild immune abnormalities as "HIV-negative AIDS," when, contrary to what the REASON authors assert, such cases would not be called AIDS today, even if HIV-positive. Duesberg has gotten a lot of mileage out of his "HIV-negative AIDS" cases (as we see), and he chooses to make his AIDS definition broad enough that as many as possible of his "AIDS" cases don't have HIV. We, however, are certainly not obligated to do the same.

In summary, if we are not allowed to use HIV status, then defining AIDS stringently in terms of an acquired worsening immune failure (a CD4 count of less than 200) still preserves the prognostic boundaries of the fatal syndrome of AIDS long familiar to the man on the street. Thomas et al. may carp about problems with official CDC AIDS definitions, but they are actually carping about modifications of official definitions which they made themselves by subtracting HIV testing. Let them make better definitions, for surely there is something perverse about choosing a definition that is so overbroad as not to be useful, then blaming the establishment that it is so overbroad as not to be useful. The important fact for the rest of us is that people dying of immune failure for no other obvious reason in body-fluid-exposed groups are invariably HIV-infected.

7) I thought the Thomas/Mullis/Johnson article an unusually bitter one for REASON to be running, since its authors suggest not only that the U.S. government has failed with AIDS but that just about everyone else has failed to think properly as well. The authors essentially suggest that the scientific method itself failed when it has come to this problem--that instead, hundreds of independent working groups in public and private labs in scores of countries are even now participating in the same shared conspiracy or mass delusion. Supposedly, every major HIV study lab has been afraid to acknowledge openly that the emperor has no clothes. Does this really seem likely to the reader? I am strongly reminded of the conspiracy theories of creationists and UFO-coverup enthusiasts when I read this kind of thing.

Although I live in the world of institutional biomedical research, I don't find it to be the same conspiratorial one I read about in the Thomas/Mullis/Johnson article. Knowing how competitive biomedical researchers are, I prefer a different explanation for the present state of AIDS understanding--HIV infection just happens to be a really hard biological problem. However, progress is being made. According to recent news reports, a second controlled study has now confirmed that sterilized plasma from well HIV-positive people improves health and extends life considerably in AIDS patients. This is just as we might expect from knowing how HIV normally escapes its host's antibody immune response in AIDS, but yet might still be susceptible to anti-HIV antibodies transferred in plasma from someone else. Globulin protein (antibody) therapy has been tried in AIDS patients in the past, but was not very helpful, apparently since it contained no anti-HIV antibodies. I predict that the success of immunologic therapies targeted specifically against HIV in AIDS is shortly to make drug-induced AIDS theories even harder to believe.

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