SUPPRESSION OF NON-SPECIFIC IMMUNITY, NOT T-IMMUNODEFICIENCY, IS THE MAIN CAUSE OF OPPORTUNISTIC INFECTIONS IN AIDS

By Vladimir Koliadin

April 1998

1. Is the immune system the main protection from opportunistic infections?

The main clinical manifestation of AIDS is severe opportunistic infections (OI) with abnormally high mortality. These diseases are of endogenous nature: the OI-causing pathogens are present in healthy organism too, though only in small quantities. Why OI develop? A natural answer is that some factor X in healthy organism stifles opportunistic pathogens, and only if it fails, these ever- present pathogens proliferate and cause OI. What plays the role of this factor X? This question central to understand the causal mechanisms of AIDS and of other forms of susceptibility to OI. It is widely accepted at present that just the immune system normally suppresses opportunistic pathogens, and just immunodeficiency causes development of OI. Moreover, this notion seems to be "self-evident": if not the immune system, what else can protect from opportunistic pathogens?

The immune system is responsible for "acquired immunity" or "specific immunity", not for immunity at all. Such specific immunity develop as reaction of the immune system to a certain pathogen, and it is directed only against this pathogen. The technical meaning of the term "immunodeficiency" is nothing but "deviation of some parameters of the immune system from the normal state", not a lack of immunity (resistance to pathogens) itself as many non-specialists believe. Immunodeficiency does not necessarily lead to decrease in immunity, and decrease in immunity is not necessarily caused by immunodeficiency. Besides the specific immunity, there are several forms of non-specific immunity, maintained by mechanisms not related to the immune system [1]. Failure of such mechanisms, technically not being "immunodeficiency", can result in increased susceptibility to pathogens (decreased immunity). The central idea in this summary is that protection from OI is carried out by these non-specific mechanisms, not by the immune system. Failure of these mechanisms, not failure of the immune system (immunodeficiency), is the actual cause of OI.

If other mechanisms of protection from pathogens, not related to the immune system, are well known [1], why is the immune system thought to be the main protection from opportunistic pathogens? Besides the "self- evidence", this belief rests on strong correlation between T- immunodeficiency and OI: many patients suffering from OI have immunodeficiency too, and this cannot be explained by random coincidence. But correlation cannot prove causation - simply because it may be caused by causal links other than "immunodeficiency causes OI": 1) OI cause T- immunodeficiency; 2) both OI and T-immunodeficiency are caused by a third factor; 3) correlation is overestimated because observations are biased. The main aim of the analytical study summarized below is to look at the known facts critically from such a vantage point, and to try to find alternative explanations to the observed correlation between T- immunodeficiency and OI. Oddly enough, after critical reevaluation, the current "immunodeficiency- causes-OI" postulate occurs to have neither experimental nor theoretical underpinning. Moreover, it even contradicts to tenets of immunology. An alternative view - that OI result from suppression of non-specific mechanisms of resistance - is capable to provide a coherent explanation to the whole body of facts known about OI, immunodeficiency, as well as about the pathogenesis and epidemiology of AIDS. Causal mechanisms of AIDS are well explainable at the level of knowledge which had been achieved by the middle of 1970s, or even middle 1960s, and need no any doubtful hypotheses about "deadly retroviruses".

2. Mechanisms of non-specific immunity to opportunistic pathogens

Human organism is permanently exposed to a great many of species of microorganisms which are present in environment. Nevertheless, most of these species cannot cause a disease because the whole set of physical and chemical conditions in organism is normally not suitable for their reproduction [1]. Such a set of conditions is determined genetically. This is perhaps the most important (but less noticeable and poorly understood) factor of resistance. This form of resistance is frequently named "innate non-specific immunity" (and by many other terms [1]) and lies beyond the scope of the current immunology. Naturally, if metabolism of the host deviates radically from the normal state (e.g. in course of a disease, intoxication, stress, etc.) such a change can made conditions suitable for some ever-present opportunistic pathogens, and OI will develop.

Even though such mechanisms of innate immunity protect organism from a great many of species, this protection is far from being universal. Many areas of the organism, especially that connected to environment (skin, mucous membranes, gut, etc.) are still suitable ecological niches for thousands of species of microorganisms, including many potentially pathogenic ones. Without some additional protection infections would be inevitable. Nature has found an elegant way to overcome this vitally important problem: competition between various species had been effectively harnessed [2]. Since the first hours and days of life of the host, these ecological niches are colonized and, then, permanently populated by many species of microorganisms. The system of these species is named "resident microflora" or "normal microflora". It is of vital importance to the host that only non-pathogenic species normally dominate in its microflora and keep potentially pathogenic ones (opportunistic pathogens) at low and safe quantities. Thus, these non-pathogenic microflora protect the host from ever-present opportunistic pathogens [2,3]. Such a symbiosis rests on the ability of the host to maintain conditions which guarantee selective advantage for non- pathogenic flora. This ability of the host is determined genetically and emerged in course of long- term natural selection.

3. What and how causes opportunistic infections

There are two types of opportunistic pathogens: the ones which are normally dormant because conditions in the host are not suitable for their reproduction, independently on presence of other species (type I), and the pathogens which are capable to replicate in conditions of healthy organism, but are normally suppressed by other species of microorganism - by non-pathogenic resident flora (type II). Hence, the causes of opportunistic infections may be also subdivided into two groups: radical changes in metabolism of the host, and some factors which suppress the non- pathogenic resident microflora - antagonists of the type II opportunistic pathogens.

Which factors are known to be capable to suppress non-pathogenic resident flora? At least three groups of such external factors are well known: 1) antibiotics, including bacteriostatic drugs (e.g. sulphonamids) and other antibacterial drugs; 2) drugs with cytotoxic effect (e.g. drugs used for anti-cancer chemotherapy, for immunosuppression) ; 3) radiation [2-5]. The most frequent causes of the OI observed in clinical practice are antibiotics, especially broad spectrum ones [5-8]. Non- pathogenic microflora, which normally dominate and overgrow pathogenic species, are more sensitive to these drugs than some opportunistic pathogens (e.g. fungi). Therefore, antibiotics create selective advantage for these pathogens by suppression of their usual antagonists - non- pathogenic bacterial flora [1, 5-8]. If two species are antagonists, even a small reproductive advantage of one of them, after a few tens of generations inevitably leads to complete dominance of this species. Thus, even a small influence may result in radical changes in balance of microflora. Such an influence should not necessarily increase reproductive ability of one species and decrease that of another. It is enough, for example, to stifle both species, but to a different extent, and the less stifled species overgrows another. Surely, in reality such interrelations are much more complex because not two but thousands of species are involved in this process. But the main feature of this ecological system remains the same - external factors may lead to radical changes in proportions of various species in microflora [5].

For the same reasons, along with the external factors affecting microflora directly, there are indirect mechanisms leading to changes in the balance of normal microflora. As far as microflora are essentially dependent on the host's metabolism (they obtain many nutrients and growth factors from the host), significant changes in the metabolism of the host (especially in catabolic direction) may lead to radical changes in the balance of microflora. If these changes are advantageous for at least one opportunistic pathogen, this species will proliferate and cause OI. Such metabolic changes can also cause OI through violation of the "innate resistance" determined by peculiarities of the normal metabolism of the host. Opportunistic viruses are likely to be activated by such metabolic changes: viral reproductive cycle essentially depends on cellular metabolism. Thus two groups of factors may cause OI: suppression of the resident non-pathogenic flora by external factors (see above), and the factors capable to cause radical changes in metabolism.

The most frequent cause of such metabolic changes in catabolic direction is stress-reaction . Such reaction is highly non-specific - it can be caused by a wide range of adverse factors: any severe disease, intoxication, psycho-trauma, protein-calorie malnutrition. It is known that stress- syndrome is mediated by elevated concentrations of corticosteroids ("stress-hormones""). Besides the stress-factors themselves, most features of the stress reaction may be induced by direct injection of corticosteroids. These hormones and their synthetic analogues are used in medicine to cope with acute inflammations (and they are frequently used to treat AIDS-patients).

4. Why opportunistic infections correlate with T-immunodeficiency

The T-immunodeficiency is well known to be an essential feature of the stress-syndrome. In the middle of 1970s it was also shown experimentally that just T4-lymphocytes (a subtype of T- lymphocytes) are most sensitive to stress-hormones corticosteroids. Hence, T-immunodeficiency at all and T4-immunodeficiency in particular are highly non-specific symptoms - they appear almost always when stress-reaction develop. It is natural that this forms of immunodeficiency are present in almost any severe enough disease or other abnormal states of organism. Mainstream AIDS-science tries to ignore these reliably established facts - mainly because the T4- immunodeficiency is promulgated as a specific feature of AIDS (see [13,14] for details).

There are several explanation for the correlation between OI and T-immunodeficiency. First, severe OI (e.g. induced by antibiotics) cause stress-syndrome. Hence, T-immunodeficiency has to be expected in such cases - as a consequence, not the cause of these OI. Second, both OI and T- immunodeficiency have common causal factors: cytostatic and cytotoxic drugs, and radiation. In individuals exposed to such factors, for example, in patients receiving anti-cancer or immunosuppressive therapy, OI can develop due to suppression of the non-pathogenic resident flora by these factors. Third, radical changes of metabolism in the catabolic reaction (e.g. caused by any form of stress, or by protein-calorie malnutrition) suppress both normal non-pathogenic flora (this causes OI) and the immune system (this causes T-immunodeficiency). Such a mechanism explains why people with severe and long-lasting diseases frequently suffer from OI as well as have signs of T-immunodeficiency. Administration of corticosteroids, even though these immunosuppressive drugs don't suppress resident microflora directly, depletes microflora indirectly - through the catabolic changes in metabolism these drugs inevitably induce. This explains why OI frequently develop in course of such therapy by corticosteroids. Thus, the strong correlation between OI and T-cell immunodeficiency is easily explainable by mechanisms other than "immunodeficiency-causes-OI".

The correlation between OI and T-immunodeficiency is likely to be overestimated due to observation bias. To establish the fact of T-immunodeficiency it is necessary to carry out some laboratory tests. Such tests are normally used only if physicians already suspect immunosuppression in this patient. As far as "immunosuppression-causes-OI" postulate is believed to be self-evident, mainly some signs of OI made physicians suspect immunosuppression and force them to carry out tests for immunodeficiency. If immunodeficiency is found, this finding is perceived as confirmation of the causal role of immunodeficiency in development of OI. Naturally, most cases of T- immunodeficiency, not associated with OI, remain unnoticed; and correlation between OI and T-immunodeficiency seems apparently high.

5. Belief in "immunodeficiency-causes-OI" as the cause of iatrogenic OI

Perhaps the most frequent cause of OI in developed countries is of iatrogenic (caused by medicine) nature. As far as immunodeficiency is thought to be the main cause of severe OI, almost any patient with severe immunodeficiency (or presumably high-risk of immunodeficiency) is put on permanent prophylaxis by broad-spectrum antibiotics. Such a prophylactic measure is thought to be capable to reduce risk of OI. Nevertheless, such long-term intake of broad- spectrum antibiotics is known to be the main cause of iatrogenic OI, and it is known that antibiotics induce OI because suppression of normal microflora [3, 6-8], not of the immune system. It is not an easy task to understand what has caused OI in such cases - immunodeficiency or antibiotics. Interpretation of the facts depends mainly on preconceived ideas. Even if OI have been caused by antibiotics, immunodeficiency is usually accepted as the "actual" cause.

Thus, the uncritically accepted "imunodeficiency-causes-OI" postulate is capable to increase dramatically the number of cases of OI through inadequate administration of broad spectrum antibiotics to some categories of patients. Naturally, this creates actual correlation between OI and immunodeficiency. Oddly enough, the same belief conceals the real causes of these iatrogenic OI: these diseases are being explained by immunodeficiency and the correlation is perceived as an additional proof for the "immunodeficency- causes-OI" dogma. Such an iatrogenic effect essentially depends on subjective estimates of the risk of OI shared by physicians. If the risk is believed to be unusually high (e.g. in AIDS patients or HIV-positives), very severe regimen of broad-spectrum antibiotics is being chosen. Naturally, probability and severity of OI is in direct relation with intensity and longevity of such "prophylaxis". In any other situation, doctors would avoid such intensive and prolonged use of antibiotics, but the belief in high risk of severe OI, forces them to leave usual precautions. It is hardly surprising that severe OI will finally develop in these patients (due to destruction of their normal microflora by antibiotics) as well as T- immunodeficiency (as stress-reaction to the OI themselves, intoxication, and psychological trauma).

6. Can the immune system stifle opportunistic pathogens?

If to accept that T-immunodeficiency is the main cause of OI, one should also admit that just the immune system plays the leading role in permanent suppression of opportunistic pathogens in healthy organism. How does the immune system carry out such protective functions? Any clear- cut explanations are conspicuously absent in medical literature. If to try to answer this "naive" question, serious inconsistencies immediately appear. Some of them are summarized below.

1) Opportunistic pathogens are not able to induce any noticeable acquired immunity even in experiments [4]. How can the immune system protect from OI if it works mainly through mechanisms of acquired immunity? 2) It is completely unexplainable how the immune system can discriminate between pathogenic and non-pathogenic species and to suppress just the pathogenic ones: both types are presented in microflora by thousands species, and both types are foreign for the immune system. 3) Opportunistic infections begin to develop in areas not easily accessible by the immune system, at least in healthy organism. How can the immune system be the factor which normally suppress opportunistic pathogens in these areas? 4) Since the first minutes of life organism is being colonized by microorganisms, and just non-pathogenic species normally dominate in this process. This means the pathogens are stifled by some factor since the very birth. How can the immune system be this factor if development of specific immune reactions need some time ( at least a few tens of hours)? Moreover, the immune system is dormant in newborns. 5) Cytotoxic T-cells, a central mechanism of the cell-mediated acquired immunity, cannot stifle opportunistic pathogens - simply because these immune cells can attack only the cells with the same genetic makeup, having the same MHC-antigens as the host [1], but microorganisms don't carry such antigens. 6) A great number of potentially pathogenic species ever-present in microflora poses one more problem: it has never been shown experimentally that specific immune reactions can be activated in respect to hundreds of foreign antigens simultaneously.

7. How epidemic of AIDS became possible

The epidemic of severe iatrogenic OI, misleadingly named AIDS, was triggered by a "fashion" of long-term use of broad-spectrum antibiotics as permanent prophylaxis of sexually transmissible diseases (STD). This fashion became popular in late 1970s in most promiscuous (having many sexual partners) gays as well is in some groups of heterosexual population with specific lifestyle marked by high level of promiscuity, heavy abuse of recreational drugs, etc. Gradual destruction of the resident flora by antibiotics resulted in development of OI, as well as in long-term diarrhea, maladsorption, weight loss - classical symptoms of antibiotic abuse [3-7]. In cases of severe enough OI T-immunodeficiency developed as a natural stress-reaction to the opportunistic disease. These cases of severe OI in gays were spotted by the CDC in 1979-1981 and erroneously explained by acquired T-immunodeficiency as the primary biological cause. Association of these cases with homosexuality and promiscuity was interpreted as a sign of infectious nature of these disease. Nobody doubted whether T-immunodeficiency was actually the cause of these severe OI. All efforts were focused at finding some external factors causing the immunodeficiency, not at the causes of OI themselves. In 1981, cases of "unusual infections" (in reality caused by antibiotics), if observed in gays, were announced as first signs of new and deadly immunodeficiency [10]. Intensive permanent prophylaxis by broad-spectrum antibiotics was prescribed to such individuals. Thus, instead of cure, they received just the disease-causing factor; this made their OI recurrent, severe, and seemingly incurable. In 1980s, the mainstream science promulgated highly non-specific symptoms as signs of AIDS (lymphadenopathy, a positive test for HIV- antibodies). This expanded dramatically the range of victims of the dangerous practice to prescribe permanent use of broad-spectrum antibiotics. Naturally the number of cases of severe OI was rapidly increasing in 1980s (and this seemingly supported the official "infectious" hypothesis). Besides the wrong deciphering this syndrome as immunodeficiency, the HIV=AIDS=death belief was also an important causal factor of the iatrogenic epidemic. This belief forced physicians to use abnormally severe regimen of antibiotics (see section 5). In 1990s, this fear gradually alleviated, and this resulted in noticeable decrease in new cases of AIDS in the middle of 1990s.

8. Which hypothesis explains facts on AIDS better?

The hypothesis on causes of OI described in sections 2-6, if applied to AIDS, is capable to explain basic features of pathogenesis and epidemiology of AIDS. But the officially accepted HIV-AIDS hypothesis also provides its own explanations. Below, some arguments are summarized which could help to decide which hypothesis is better compatible with facts.

1) Abnormally long and intensive use of broad-spectrum antibiotics is a factor common to all AIDS patients and many HIV-positives, irrespective to the group of population they belong too. On the other hand, such regimen of antibiotics is extremely rare in other categories of patients and in population at large.

2) In many cases of AIDS, severe OI are observed earlier than any noticeable T4- immunodeficiency. As for mild OI, such as thrush, these infections are observed earlier than immunodeficiency in most cases of AIDS. If the immunodeficiency is actually the cause of OI, how can the consequence precede the cause?

3) Such typical symptoms of AIDS as diarrhea, maladsorption, weight loss are also typical to suppression of the friendly microflora of the gut. This suppression is a natural effect of antibiotics. It also may be caused by substances with cytostatic effect (AZT is an example of such a substance). As for the HIV-AIDS hypothesis, no any coherent explanations were provided how HIV can cause these symptoms.

4) If immunodeficiency is actually the main problem in AIDS, why do the patients suffer mainly from opportunistic (endogenous) but not from usual (exogenous) infections?

5) The official HIV=AIDS hypothesis fails to explain why male homosexuals are the main victims of AIDS. The mainstream science tries to explain this essential feature of AIDS by radical difference in probability of transmission of HIV during homo- and heterosexual contacts. Even if to assume that HIV is transmissible, the difference is maximum 2-fold [11]. Anal sex is quite popular in heterosexual pairs, and heterosexual population is many times larger than homosexual. Nevertheless, AIDS is not associated with heterosexual anal sex [15].

6) The HIV-causes-AIDS theory cannot explain why AIDS is highly associated with promiscuity. Probability of transmission of HIV is estimated as 1-2 in 1,000 contacts. With such a low rate of transmission in one intercourse, spread of infection should not depend on promiscuity. For example, if one infected person changes sexual partners after each intercourse (maximal level of promiscuity), another infected person - only after 100-200 intercourses (low level of promiscuity), the average number of partners infected after a great number of contacts will be almost the same for the two infected individuals [12]. On the other hand, promiscuity is directly associated with antibiotics (treatment and/or permanent prophylaxis of STDs).

7) The official hypothesis fails to explain why AIDS is distributed very unevenly over the globe. For example AIDS (not HIV-seropositivity) is extremely rare on the territory of the former Soviet Union in spite of higher incidence of STD and about the same number of male homosexuals as in the USA. It is essential that long-term prophylactic use of antibiotics is very unpopular among physicians in the former Soviet Union.

8) Drug-resistant strains of microorganisms are frequently detected in AIDS patients, and just this drug- resistance is partially responsible for the frequent lethal outcome of opportunistic infection incurable by antibiotics. There is no any visible link between immunodeficiency and drug- resistance of the microorganisms. On the other hand, drug-resistance is a natural consequence of antibiotic abuse - it results from natural selection of drug-resistant mutants under the selective pressure of antibiotcs [3]

Conclusions

The ever-present opportunistic pathogens are normally stifled by mechanisms of non-specific resistance - mainly by non-pathogenic microflora, not by the immune system. Failure of these mechanisms, for example suppression of the resident flora by antibiotics, is the main cause of opportunistic infections. The widely shared postulate, that T- immunodeficiency causes opportunistic infections, has neither theoretical nor factual underpinning. T-immunodeficiency is well known to be a secondary phenomenon and a typical symptom of catabolic stress. Epidemic of AIDS is of purely iatrogenic nature - its main cause is antibiotic abuse. The epidemic resulted from wrong interpretation of the syndrome as acquired T4-immunodeficiency in early 1980s. Non- specific symptoms were announced as first signs of these disease, and individuals with such symptoms were put on permanent prophylactic use of broad spectrum antibiotics. All the symptoms of AIDS, including severe opportunistic infections, are caused by this abuse of antibiotics.

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