A Critical Analysis of the HIV-T4-CELL-AIDS Hypothesis - Excerpt version

Eleni Papadopulos-Eleopulos,¹ Valendar F.Turner,² John M. Papadimitriou,³ David Causer,¹ Bruce Hedland-Thomas,¹ & Barry Page¹
1: Department of Medical Physics, 2: Department of Emergency Medicine, Royal Perth Hospital, Perth, Western Australia; 3: Department of Pathology, University of Western Australia.

T4 and the clinical syndrome

The HIV/AIDS researchers consider T4 decrease as being the "hallmark" and "gold standard" of HIV infection and AIDS (Shaw et al., 1988; Levacher et al., 1992). In fact, in the most recent (1992) CDC AIDS definition, an AIDS case can be defined solely on serological, (positive HIV antibody test), and immunological (T4 cell count less than 200 X 106/L), evidence (CDC, 1992). The new definition also requires that "the lowest accurate, but not necessarily the most recent, CD4+ T- lymphocyte count should be used" to define an AIDS case (CDC, 1992). However, ample evidence exists that T4 cell decrease can be induced by many factors, some trivial, such as sun bathing and solarium exposure, a decrease which can persist for at least two weeks after exposure has ceased (Hersey et al., 1983; Walker & Lilleyman, 1983). T4 cell counts "can vary widely between labs or because of a person's age, the time of day a measurement is taken, and even whether the person smokes" (Cohen, 1992). That many factors can affect the T4 cell number is reflected by their large variation in HIV positive patients. In one such study, patient measurements repeated by one laboratory within 3-days showed a "minimum CD4+ cell count of 118 cells/mm3 and a maximum CD4+ cell count of 713 cells/mm3" (Malone et al., 1990). In the MACS, consisting of 4954 "homosexual/bisexual men", it was stressed that physicians and patients should be "aware that a measured CD4 cell count of 300X106/L really may mean it is likely that the "true" CD4 cell state is between 178 and 505X106/L. Thus there is no certainty this person's "true CD4" is less than 500X106/L or that it is greater than 200X106/L" (Hoover et al., 1992). It is important to note that these variations were obtained despite the fact that the CD4 measurements were undertaken in laboratories which "are carefully standardized in an ongoing quality control program".

In a study (Brettle et al., 1993) which examined the impact of the 1993 CDC AIDS definition on the annual number of AIDS cases as compared to the 1987 definition, it was found that if the definition was based on:

(i) the "first of two consecutive CD4 cell counts < or equal to 200 X 106/L", the number of AIDS cases doubled;

(ii) one abnormal CD4 count, the number of AIDS cases trebled.

Researchers at the University of California at Los Angeles School of Medicine found that 5% of healthy persons seeking life insurance had abnormal T4 cells counts, and that "In a subgroup of patients, the low T-cell numbers or ratios appear to be stable findings". They concluded: "In the absence of a history of a specific infection or illness or major abnormalities on a physical examination, it is not worthwhile to attempt to find a specific cause for the abnormality of T- cell subsets...A uniform approach to this problem throughout the medical community will help alleviate patients' anxiety and reduce the concern of the insurance industry about this relatively common problem" (Rett et al., 1988).

If LAS, ARC, and the AIDS indicator diseases such as KS and PCP are the consequence of T4 cell depletion then all groups of people who have a low T4 cell count, irrespective of cause, should have high frequencies of opportunistic infections and neoplasms. Conversely, all patients with AIDS indicator diseases should have abnormally low T4 cells.

In a study on the effects of blood transfusion on patients with thalassaemia major, researchers at the Cornell University Medical Center and the Sloan-Kettering Institute for Cancer Research observed decreased T4 cell numbers and inverted T4/T8 ratios associated with the transfusions, but no increase in KS or PCP, and concluded that "...studies which define transfusion related AIDS on the basis of analyses with monoclonal antibodies must be viewed with caution" (Grady et al., 1985). Although patients with alcoholic liver disease do not develop KS, PCP and other AIDS indicator diseases more often than usual, they have both immune deficiency and positive HIV antibody tests leading researchers from the Veterans Administration Medical Centre to stress the importance of recognising these facts: "...lest these patients be falsely labelled as having infection with the AIDS virus and suffer the socioeconomic consequences of this diagnosis" (Mendenhall et al., 1986).

Patients who have malaria have severe immunoregulatory disturbances including decrease in T4 cells. A significant number of these patients also test positive for HIV but they do not develop the AID clinical syndrome, leading Volsky et al to conclude, "exposure to HTLV-III/LAV or the related retrovirus and the occurrence of severe immunoregulatory disturbances may not be sufficient for the induction of AIDS" (Volsky et al., 1986).

The MACS in the USA showed that "even in the absence of treatment, close to 25, 15 and 10% of men were alive and asymptomatic 4, 5 and 6 years after first CD4+ <200 X 106/L measurement" (Hoover, 1993). In the same study comparing HIV positive individuals who within five years progressed to AIDS (Group A) with that those who did not (Group B), it was found that: "receptive anal intercourse both before and after seroconversion with different partners was reported more frequently by men with AIDS. The ratio of the differences in this sexual activity between groups A and B was higher at 12 (2.3) and 24 (2.6) months after seroconversion than before seroconversion (2.0)". It was concluded that "sexually transmitted co-factors, preseroconversion and/or postseroconversion...augment (or determine) the rate of progression to AIDS" (Phair et al., 1992). However, since:

(a) sexually transmitted infectious agents are bi- directionally transmitted, that is, from the active to the passive partner and vice-versa;

(b) in the above study the only sexual act directly related to the progression to AIDS was passive anal intercourse (unidirectionally);

one would have to conclude that the "co-factors that augment (or determine)" progression to AIDS are non-infectious. These findings are in agreement with the oxidative theory of AIDS which claims that both HIV phenomena (RT, virus-like particles, antigen/antibody reactions, "HIV-PCR") and AIDS are caused by the many oxidative agents (including semen), to which the AIDS risk groups are exposed (Papadopulos-Eleopulos, 1988; Papadopulos-Eleopulos et al., 1989a; Papadopulos-Eleopulos et al., 1992a; Papadopulos-Eleopulos et al., 1992b) [PCR=polymerase chain reaction].

According to Canadian researchers, "In TB as well as in lepromatous leprosy, an immunosuppressive state will frequently develop in the host. This state is characterised by T lymphopenia with a decreased number of T helper cells and an inverted T-helper/T-suppressor cell ratio ...immunosuppression induced by the infection with M.tuberculosis can persist for life, even when TB is not progressive" (Lamoureux et al., 1987). Yet these patients do not have high frequencies of KS, PCP or other AIDS indicator diseases. In other words, decrease in T4 cells is not sufficient for the AIDS indicator diseases to appear. This is also supported by evidence from animal studies. Experimental depletion of T4 cells in mice used as models for systemic lupus erythematosus in humans did not lead to increased frequencies of neoplasms, nor did mice "develop infectious complications, even though they were housed without special precautions". In fact mice with low T4 cell numbers had "prolonged life" (Wofsy & Seaman, 1985) It is also of interest that despite the indispensable role attributed to T4 and T8 lymphocytes in antibody production (helper and suppressor respectively), AIDS patients in the presence of low numbers of T4 cells and high numbers of T8 cells, have increased levels of serum gammaglobulins, and are not hypogammaglobulinaemic as might be expected. Also, although human umbilical cord T-cells produce suppressor factors(s), the factor(s) is produced by T8- (T4+) not T8+ cells (Cheng & Delespesse, 1986). Thus, T4 and T8 cells do not seem to possess the generally accepted functions attributed to them.

According to the HIV theory of AIDS pathogenesis, "The Human Immunodeficiency Virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), has the capability of selectively infecting and ultimately incapacitating the immune system whose function is to protect the body against such invaders. HIV-induced immunosuppression results in a host defense defect that renders the body highly susceptible to "opportunistic" infections and neoplasms" (Fauci, 1988). Decrease of T4 cells to approximately 200X106/L leads to the development of "constitutional symptoms", and to less than 100X106/L to "Opportunistic diseases" (Pantaleo et al., 1993). If this is the case then:

1. In all individuals with "constitutional symptoms", OI and neoplasms, the T4 cell number should be abnormally low;

2. The decrease in T4 cells should precede the development of the clinical symptoms since: (a) the cause must precede the effect; (b) for many neoplastic and infectious diseases, there is evidence that the diseases themselves and the agents used to treat them may induce immune suppression including decreased numbers of T4 lymphocytes and reversal of T4/T8 ratios.

This is not the case even for the most serious and characteristic of the AIDS diseases, KS and PCP. In the MACS it was reported that:

(a) "...persistent generalised lymphadenopathy was common but unrelated to immunodeficiency", and "Although seropositive men had a significantly higher mean number of involved node groups than the seronegative men (5.7 compared with 4.5 nodes, p<0.005), the numerical difference in the means is not striking".

(b) weight loss, diarrhoea, fatigue, fever, which constitute the "wasting" syndrome, (which at present is an AIDS indicator disease), night sweats, herpes zoster, herpes simplex (another AIDS indicator disease), oral thrush, fungal skin infections and haematological abnormalities, were present in both seronegative and seropositive individuals, although some of them were present at higher frequencies in the latter group. A relationship was found between thrush, anaemia, fever and neutropenia and T4 cell deficiency. However, "the clinical abnormalities were considerably better at reflecting concurrent CD4 lymphocyte depression than the low CD4 lymphocyte counts were at determining clinical involvement" (Kaslow et al., 1987). These observations are just as compatible with the hypothesis that T4 lymphocyte deficiency is the result and not the cause of the observed clinical abnormalities.

KS, the main reason for which the retroviral hypothesis was put forward, was initially postulated to be caused by infection of normal cells with the retrovirus. When, late in 1984 it became clear that the KS cells were not infected with HIV, it was generally accepted that the disease was caused by HIV indirectly, that is, as a consequence of T4 cell decrease.

At present, it is generally believed that KS is caused by "a specific sexually transmitted etiologic agent" (Beral et al., 1990; Weiss, 1993) other than HIV, but "immune suppression (both in AIDS and in transplant patients) is the dominant cofactor for subsequent disease" (Weiss, 1993). However, unlike the Unites States CDC and most AIDS centres around the world, for the Walter Reed Army Institute of Research "...the presence of opportunistic infections is a criterion for the diagnosis of AIDS, but the presence of Kaposi's sarcoma is omitted because the cancer is not caused by immune suppression..." (Redfield & Burke, 1988) In a study by a group of researchers from Amsterdam regarding the relationship between the T4 cell number and the development of the clinical syndrome, KS was excluded "Because Kaposi's sarcoma may manifest at higher CD4+ lymphocyte counts than other AIDS- defining conditions" (Schellekens et al., 1992). This is not surprising since by the beginning of the AIDS era, the immune surveillance hypothesis of carcinogenesis had been already refuted (Kinlen, 1982). In fact, the presently available data indicate that KS in all individuals, including gay men, may be caused by a non-infectious agent (Papadopulos-Eleopulos et al., 1992a). Even in the early stages of the AIDS era, it was reported that KS in gay men appeared following corticosteroid administration (which was administered for diseases totally unrelated to HIV or AIDS) and resolved when the drug was discontinued (Schulhafer et al., 1987; Gill et al., 1989). Thus the HIV/AIDS hypothesis cannot account for the very disease for which it was originally put forward.

In a study of 145 patients, 97% of whom were homosexuals, with biopsy proven PCP at St. Vincent's Hospital and Medical Centre, New York, 17% of AIDS patients had a T4 cell count higher than 500/mm3, and a further 14% between 301-500/mm3, "in addition, patients with T4-T8 ratio greater than 1.0 and those with total T4 lymphocyte counts greater than 500/mm3 cells did not show improved survival compared with patients with abnormal values....the degree of suppression did not influence mortality (Kales et al., 1987). Researchers from the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, studied 100 HIV-infected patients "who had 119 episodes of pulmonary dysfunction within 60 days after CD4 lymphocyte determinations". T4 cells were less than 200X106/L before 46 of 49 episodes of PCP, 8 of 8 episodes of CMV pneumonia, 7 out of 7 Cryptococcal neoformans pneumonia, 19 of 21 episodes of Mycobacterium avium-intracellulare pneumonia, 6 of 8 [pulmonary] KS and in 30 out of 41 non-specific interstitial pneumonia. However, "Before the 119 episodes of pulmonary dysfunction were diagnosed in this study, the HIV- infected patients had manifested the following clinical HIV- related disorders: no disorders (4 episodes), Kaposi's sarcoma without opportunistic infections (68 episodes), life- threatening opportunistic infection (44 episodes), other AIDS- related conditions (11 episodes)". In addition before the diagnosis of the pulmonary episodes the patients had received: "zidovudine (36 episodes), interferon (23 episodes), recombinant interleukin-2 (3 episodes), cytotoxic chemotherapy (16 episodes), dideoxycytidine (6 episodes), muramyl tripeptide (1 episode), suramin (6 episodes), heteropolyanion 23 (5 episodes), zidovudine plus interferon (5 episodes), nonablative bone marrow transplantation (4 episodes). Twenty- two episodes occurred in patients who had been receiving neither experimental therapy nor zidovudine" (Masur et al., 1989). These data may be interpreted as showing that in some types of "pulmonary dysfunction", most cases (but not all) appear to be preceded by a CD4 count <200X106/L. However, given the well known fact that malignant neoplasms, infectious diseases and the administration of chemotherapeutic agents may themselves cause immunosuppression (Serrou, 1974; Oxford, 1980; Reinherz et al., 1980; Rubin et al., 1981; Thomas, 1981; Weigle et al., 1983; Williams et al., 1983; Kempf & Mitchell, 1985; Feldman et al., 1989), it is equally plausible to argue that both "pulmonary dysfunction" and the low CD4 cell counts observed in patients were the result of their recent past illnesses and previous exposure to prescribed and illicit drugs and other factors.

In a recent study it was found that 3 patients who developed PCP within 8-14 days of "symptomatic, primary HIV infection", had normal T4 cell numbers and T4/T8 ratios 50-90 days before they became symptomatic. During the symptomatic phase the T4 cell count dropped to 62-91 cells/uL. However, "Within four months of symptom onset, their CD4 counts and CD4/CD8 ratios returned to normal". In two of the patients, a bisexual man and a gay man, "HIV-1 antibodies were detectable by EIA and WB" 30 days after these two individuals became symptomatic [EIA=ELISA].

"Twenty-nine to forty-eight months after acquiring HIV-1 infection", all three patients still had normal T4 cell numbers and were asymptomatic. The authors concluded "profound CD4 lymphocytopenia can revert to normal without antiretroviral therapy" and stressed "it is important that such cases are not misdiagnosed as AIDS" (Vento et al., 1993).

That no relationship exists between OI and T4 depletion was confirmed in a recent study where it was shown that "The appearance of OI and wasting syndrome was independent of T4 cells count" (Alejandro et al., 1991), as well as other studies which show that the OI may appear in the presence of normal T4 cell numbers (Stagno et al., 1980; Martinez et al., 1991; Felix et al., 1992).

In conclusion, decrease in the number of T4 lymphocytes irrespective of how it is induced, that is, by destruction of the T4 cells or by a phenotypic change, and of its cause, is neither necessary nor sufficient for the appearance of KS and OI including PCP, that is, of the clinical syndrome.