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In 1993, the widely accepted ideas that a positive test for HIV-antibodies is specific (i.e. means HIV-infection) and that HIV exists as an exogenous retrovirus were challenged by Papadopulos-Eleopulos et al. (Perth Group) [1]. Then these views were developed by the same [2] and other authors [3,4]. Neither experimental nor even logical arguments were advanced by mainstream AIDS-scientists to disprove the central points of the Perth Group [1,2] *. At present, it is still accepted in mainstream AIDS-science that existence of HIV and high specificity of HIV-antibody tests are ultimately proven scientific facts. Besides conformity of thinking and vested interests, this belief is maintained due to the absence of clear-cut alternative explanations for the phenomena which are thought to prove the HIV-causes-AIDS theory. Some important questions have not been answered. If HIV does not exist, what causes a positive test for HIV-antibodies? Why are almost all AIDS-patients seropositive while almost all healthy individuals are not? Why is the positive test strongly associated with high mortality and susceptibility to opportunistic infections?
At the heart of any HIV-antibody test are the so called HIV-proteins. These proteins are produced by cell-cultures of human lymphocytes. According to the mainstream AIDS-science, these proteins belong to a new retrovirus HIV, by which these cell-lines are presumably infected. HIV-skeptics say that these proteins are of endogenous (intracellular) nature [1]. Following the facts and basic principles of immunochemistry, the only conclusion which may be drawn from a positive test for HIV-antibodies is that some immunoglobulins in the tested blood-serum have bound to these "HIV-proteins". This is the case for both ELISA and Western Blot (WB) tests, as well as for any other immunochemical test. The point of disagreement is how to interpret such binding. Mainstream science insists that such binding is due to specific antibodies, produced by the immune system after it comes in contact with HIV. The Perth Group [1,2] explain this binding by cross-reactions between "HIV-antigens" and antibodies to other non-HIV antigens, to which AIDS- patients and individuals from high-risk groups are exposed. Such cross-reactions are well known to occur when different antigens share common parts ("antigen determinants"). In this case, antibodies to one such antigen are capable of binding selectively to another antigen with the same antigenic determinants. Nevertheless, the cross-reactivity hypothesis suffers from one problem: how to explain that almost all AIDS-patients and many people in high-risk groups have been exposed to some antigens bearing common determinants only with "HIV-antigens"? Why almost everyone beyond the risk- groups have not been exposed to such antigens, although anyone in the course of his/her life has been exposed to many antigens (vaccinations, infections, etc.)?
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In the middle of the1980s, it was shown experimentally that a test for HIV-antibodies is positive in a great proportion of patients with a diagnosis of AIDS or pre-AIDS, while it is negative in almost all perfectly healthy individuals. It should be noted that AIDS-diagnosis in these patients was established from clinical symptoms, not from the HIV-test itself. This undermines the "circular definition" argument advanced by some AIDS-dissidents. Moreover, such studies were carried out according to a blind and randomized protocol [9]. This gave great credibility to the HIV-causes-AIDS viewpoint. Do such studies actually prove that HIV- positivity is specific to AIDS? Even though it may seem "self-evident" at first sight, it is not so. An important principle of evidence-based science was obviously violated in these studies: the control group was not matched to the AIDS group - perfectly healthy individuals were used as controls [1].
Why is the principle of matched control so important? The following simple example may help illustrate why. Take a disease that is characterized by some feature, say by elevated body temperature. A study shows each of 1,000 patients with this disease demonstrates high temperature, whilst each of 1,000 healthy controls - normal (lower) temperature. Does it mean that elevated body temperature is specific to this disease? Surely not - simply because the high temperature, though being highly unusual in healthy individuals, is typical to many other diseases. For the same reasons, the ability of HIV-test to discriminate between AIDS-patients and healthy individuals cannot prove specificity of HIV-tests. This obvious flaw in the studies of "specificity of HIV-antibody tests", spotted by the Perth Group [1], was ignored by the mainstream science. Which symptoms in AIDS-patients should be matched in the control group? It is not an easy question: many symptoms and signs are typical to AIDS. The Perth Group did not specify such symptoms. In the next section an attempt will be made to fill this gap.
Among other studies carried out with large number of individuals (applicants for US military service) specificity of HIV-tests has been reported as high as 1 false positive reaction in more than 135,000 [5]. Nevertheless, these studies have nothing to do with proofs of existence of HIV or specificity of HIV-antibody tests because only WB test systems were used as the "gold standard" of HIV. All these studies demonstrated is that results provided by some ELISA systems in multistep testing algorithms are well compatible with results of WB tests, at least in a population with a predicted very low prevalence of HIV-seropositivity. The unknown specificity of the "confirmatory" WB-tests themselves was not addressed in these studies.
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If HIV-antibody tests are positive in AIDS-patients and negative in healthy controls, does it mean that blood-serum of AIDS patients contains some factor which is absent in healthy individuals? Most scientists (aside from specialists in practical immunochemistry), let alone laymen, may believe that at least this fact was proven beyond any reasonable doubt by such studies. Nevertheless, this is not the case: blood-serum from healthy individuals is also capable of testing positive by WB. The only difference is that titers of this reaction are higher for AIDS-patients than for healthy controls. The titer is the maximal dilution of the serum for which reaction is still noticeable. For example, R.Gallo and his group managed to obtain "specificity" (in respect to healthy controls) only after 500-fold dilution of the serum [6,7]. Thus, blood serum from healthy controls provides positive WB-test results when diluted less than 1:500. In practical immunochemistry, such a phenomenon is explained by binding of non-specific immunoglobulins, which are present in any individual and bind to almost any antigen. In commercial WB-systems this effect is not noticeable because sensitivity is artificially lowered to avoid positive reactions in healthy individuals.
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There are several reasons to assume that tests for "HIV-antibodies" are positive in AIDS-patients due to non-specific immunoglobulins. First, it is well known that total concentrations of non- specific immunoglobulins are much higher in almost all AIDS-patients than in healthy individuals. This condition, named hypergammaglobulinemia, is highly non-specific and observed in many diseases and abnormal states of organism. Thus, the principle of matched control is obviously violated in the aforementioned studies - not healthy individuals, but patients with hypergammaglobulinemia (but without AIDS) needed to be used as controls. Second, in many AIDS patients, titers of "HIV-antibodies" are low. Perhaps for these reasons information about titers is conspicuously absent in AIDS-literature. For example, in Russia, due to shortage of test systems the so called "pool-method" was frequently used - when blood from several individuals was mixed and tested. It was noted, that even such 2-8 fold dilution of the serum, may have resulted in a false negative test [8]. Thus, titers of putative "HIV-antibodies" in some AIDS patients are about 1:2 - 1:8. In immunology such low titers are usually not considered as significant at all [9] **. Third, AIDS patients and individuals from groups at high risk of AIDS are known to be seropositive in respect to many other antigens (e.g. hepatitis-B virus, EBV, etc.). Even though this is usually interpreted as a sign of infection by these pathogens, it is also well explainable by non-specific reactivity of the serum of these individuals [3].
Non-specific reactivity should not be confounded with cross-reactivity [3]. Cross-reactivity is a specific phenomenon, well understood in immunology. Even though cross-reacting antigens differ, they share common determinants, and reaction is specific in respect to these determinants. Normally only a small proportion of antigens cross-react to antiserum against a given antigen. In contrast to cross-reactions, neither mechanisms of production nor properties of non-specific immunoglobulins are understood in modern immunology. Textbooks of immunology are either silent or say only a few words about their existence. It is also rarely mentioned in the textbooks, that only a part, maximum 20-30 percent, of the immunoglobulins produced by B-cells in response to an antigen are capable of binding specifically to the antigen; the other 70-80% of the immunoglobulins are non-specific [10]. A hypothesis has been advanced that the affinity of non-specific immunoglobulins increases radically if the B-lymphocytes are over-stimulated and that just this effect leads to positive tests for HIV-antibodies [3].
The problem of non-specific immunoglobulins is exacerbated in the tests which are based on "sandwich" principle (as in ELISA and WB). In these test-systems, the antigen (e.g. "HIV- antigen") is attached to a surface and forms the first layer in the "sandwich". After exposure to the tested serum, immunoglobulins from the serum bind to the antigen and form the second layer in the "sandwich". To detect these immunoglobulins and estimate their quantity the two-layer sandwich is subject to one more procedure - exposure to antibodies against human immunoglobulins (which are obtained from laboratory animals immunized by human immunoglobulins). These animal antibodies bind to the human immunoglobulins and form the third layer of the sandwich. Only the amount of the animal antibodies bound to human immunoglobulins, not the quantity of the human immunoglobulins themselves, is being measured in test-systems of this sort [9]. It is tacitly postulated that affinity (ability to bind) of the animal antibodies to human immunoglobulins is about the same for all individuals and, hence, the amount of the animal antibodies bound is simply proportional to the amount of human immunoglobulins. But this is not the case if non-specific immunoglobulins from some individuals are capable of binding more strongly to various substances than immunoglobulins from healthy controls. Let us say, for example, that non-specific affinity of non-specific immunoglobulins increased 3 times in respect to various proteins, including both "HIV-antigens" and animal antibodies. Then, the number of molecules of human non-specific immunoglobulins bound per one molecule of the antigen is 3 times higher. After exposure to animal antibodies, 3 times higher number of molecules of the animal antibodies will be bound per one molecule of human immunoglobulins. Thus, the total amount of animal antibodies will be 9 times (3 multiplied by 3) higher, not 3 times. Hence, even a moderate increase in non- specific affinity of immunoglobulins may lead to radical increase in the titers and, hence, to HIV-seropositivity.
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Along with the above mentioned factors, one more factor of antigen overload deserves closer attention - prolonged use of broad spectrum antibiotics. Such antibiotic abuse is closely associated with high promiscuity (frequent change of sexual partners): antibiotics used to treat frequent STDs as well as permanent prophylaxis of STDs (a fashion popular among promiscuous individuals). Moreover, permanent use of broad spectrum antibiotics is prescribed to many HIV-seropositive individuals and to most AIDS-patients as an apparent prophylaxis against opportunistic infections. Antibiotics cause antigen overload indirectly. These drugs suppress the friendly bacterial flora of the gut. These flora are of vital importance for digestion of food as well as for stifling various opportunistic pathogenic microorganisms. Suppression of the friendly flora of the gut by antibiotics results in serious problems with digestion of food and the development of opportunistic intestinal infections [14]. Such intestinal abnormalities frequently cause increased permeability of the gut walls ("leaky gut syndromes") [15]. Proteins are essential parts of our diet, and they are very powerful foreign antigens. Why don't they cause antigen overload in healthy individuals? Normally, proteins are digested into short fragments which are not antigens (cannot induce immune response), and only these non-antigenic short fragments permeate the gut walls and run into the blood stream. Abnormally high permeability of the gut walls makes it possible for molecules of proteins themselves to run into the blood stream and to become a powerful factor of antigen overload. This mechanism provides a plausible explanation for the epidemiological association between promiscuity, diagnosis of AIDS, and HIV-seropositivity, mediated by a common factor - antibiotic abuse. It also explains the unusually high rate of HIV-seropositivity in Africa, where intestinal infections are rampant.
Besides the role of foreign antigens, there is another plausible hypothesis advanced; it holds that both typical signs of AIDS - hyperactivation of B-cells and T4-lymphocytopenia - are intrinsic features of the classical stress-syndrome [11]. Stress-syndrome is a highly non-specific reaction of the organism to various adverse factors: diseases, intoxication, psychological trauma, etc. This reaction is mediated by elevated concentrations of corticosteroids ("stress-hormones"), and it may be induced by direct injection of corticosteroids. (Incidentally, corticosteroids are frequently used to treat inflammatory conditions in AIDS-patients.) If this hypothesis is combined with the aforementioned one (that hyperactivation of B-cells results in increased affinity of non-specific immunoglobulins), it provides a coherent explanation of why people with severe opportunistic infections (named AIDS) usually demonstrate T4-lymphocytopenia and HIV-seropositivity.
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In a study conducted in a rural population of Uganda (Lancet 1994, 343, 1021-23), about 10,000 individuals were tested for "HIV-antibodies". In those aged 13-44 years, 9.6% were found HIV- seropositive. During follow up, mortality was estimated as 96/1000 man-years (=96 persons out of 1000 in 1 year) in the HIV-positive group, and as only 1.4/1000 m.-y. in the HIV-negative group. Thus, mortality in HIV-seropositives was 60 times higher than in their HIV-negative counterparts. At first sight, these results seem to be a reliable proof for a causal role of HIV in AIDS, specificity of HIV-tests, and reality of HIV. For this reasons these results are frequently referred to by proponents of the HIV-AIDS theory (see for example [12,13]).
Let us look at the data from another standpoint, and consider an alternative hypothesis - that a positive "HIV-test" is only a non-specific marker of various infectious diseases. Such a "marker-effect" is likely to be caused by the elevated concentrations of non-specific immunoglobulins and an increase in their non-specific affinity associated with infectious diseases, especially multiple infections and intestinal ones (see section 4). Such diseases are known to be the main cause of mortality in this region, at least in relatively young ages. If HIV-seropositivity is actually only a marker of these diseases, most sick individuals in this population have to fall into the HIV- seropositive group. Hence, mortality in the HIV-seronegative group has to be much lower than the usual mortality rate in this region. On the other hand, if HIV-tests actually detect a new pathogen (HIV) and HIV causes additional mortality (as the mainstream AIDS science holds), mortality in the HIV-negative group should not decrease in the course of the HIV-epidemic. Thus, comparison of mortality in the HIV-negative group with its usual rate, observed before the hypothetical HIV-epidemic, can easily discriminate between the two hypotheses.
What is the usual mortality in this population? Even though reliable information about mortality in Uganda is absent, it is well known that a great proportion of population there usually die from various diseases at relatively young ages, as was the case long before the hypothetical HIV-epidemic. Is a mortality rate of 1.4/1000 in the HIV-negative group compatible with such information? The mortality rate of HIV-negative Ugandans at age 13-44 is even lower than mortality in the USA observed in the pre-AIDS era; in 1980, 157,685 deaths were registered in the USA at ages 15-44, and the population of this age group was 105,203,377. This gives a general mortality rate 1.5/1000. It is unreasonable to believe that the usual mortality in a rural population of Uganda is about the same as in the USA - one of the most prosperous countries in the world [16]. It is not compatible with the reality that a great proportion of Africans die and died young. Thus, mortality in the HIV-negative group (1.4/1000 m-y) is significantly lower than the usual mortality in this region. In other words the "HIV-test" selects a great proportion of individuals who would die regardless of the hypothetical "HIV-epidemic". This is in perfect agreement with the "HIV-is-only-a-marker" hypotheses.
Proponents of the HIV-AIDS theory [12] insist that the 9.3/1000 m-y mortality in the 13-44 age group at large is significantly higher than in other parts of the country, and this cannot be explained by causes other than HIV. Such argumentation is flawed - simply because the region was selected for this study because of its higher mortality than in other regions of Uganda. There are many other possible causes for the increase in morbidity and mortality from infectious diseases in some areas of an African country. Irrespective of the actual causes of this increase, both hypotheses predict much higher mortality in the HIV-seropositive group than in the HIV- negative one, and the causes of this difference cannot be discriminated by either hypotheses. Nevertheless, mainstream AIDS-scientists try to present this difference as a proof of the official HIV-causes- AIDS hypothesis. For some reasons, they "forget" to pay attention to the mortality rate in the HIV-negative group, which is obviously lower than the usual rate in this region - in perfect agreement with the "HIV-is-only-a-marker" hypothesis and contradicting the "HIV-causes-AIDS" one.
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The main problem with the official HIV-causes-AIDS theory is that it has never been shown that "HIV-proteins" are related to a virus. The only thing known for sure is that these proteins are produced by human lymphocytes in certain conditions in vitro (in a test tube). To the same extent, they may be produced by the lymphocytes in vivo (in living organism). The "HIV-proteins" are likely to be of cellular (endogenous) nature [1] - that is, to be encoded in the human genome by normally inactive genes ("inactive gene" means that the protein encoded by this gene is not produced by the cell). It is well known that only a small proportion of genes in the human genome are active, and different sets of genes are active in different types of cells (even though the genome is the same for all cells of a given organism). Even in cells of the same type some genes can be switched on (or off) if conditions change. The mechanisms which switch genes on and off are poorly understood in modern biology. If in some abnormal conditions lymphocytes start to produce the "HIV-proteins" (the corresponding genes are switched on), these proteins will be "foreign" for the immune system and specific antibodies will be produced against these proteins. Naturally, blood serum of such individuals will yield specific reaction to the "HIV-proteins". In other words, specific antibodies against "HIV-proteins" may be only a marker that corresponding genes have switched on due to some metabolic changes. Thus, existence of HIV cannot be proven by immunochemical and serological methods - irrespective of whether HIV-seropositivity is caused by non-specific immunoglobulins or by specific antibodies.
Even if it were proven rigorously that HIV exists as an exogenous transmissible agent (this has never been done [1-4]) and that HIV-seropositivity is caused by HIV-infection, it still cannot prove that HIV is the cause of AIDS. Correlation between HIV-infection and AIDS-defining diseases is equally explainable by the "HIV-is-a-marker" hypotheses, which hold that HIV is a benign passenger virus [17] and can easily infect only individuals with some deviations from normal health status, thus, being only a marker of such deviations. In this case, morbidity and mortality may be much higher in HIV-positive individuals than in their HIV-negative counterparts, but not because of HIV-infection. Critical reevaluation of the studies carried out in Africa (see section 5) demonstrates that the results support the "HIV-is-only-a-marker" hypotheses, and contradict the HIV-causes-AIDS one irrespective of the actual causes of HIV-seropositivity.
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