Department of Medical Physics, Royal Perth Hospital, Western Australia, 6001,
Valendar F Turner, John Papadimitriou, Barry Page, David Causer, Helman Alfonso, Sam Mhlongo, Todd Miller, Christian Fiala
Send response to journal:
"MECHANISM BY WHICH HIV CAUSES AIDS"
In his rapid response "CD3 CD4 and all the more modern names…", 3 September, Nicholas Bennett wrote: ""Can the Perth Group refute the brief explanation I offered a few weeks ago of the mechanism by which HIV causes AIDS….".
In his rapid response: "Re: "HIV" and KS", 18 August, Nicholas Bennett wrote: "The mechanism of AIDS, if I may be so bold as to spell it out for them, is roughly as follows.
HIV infection - > immediate CD4 cell loss through:
Trafficking to Lymph nodes (activated T cells traffic)
Cell death (HIV is cytotoxic to T cells)
Immune responses then become established:
Cell death due to HIV decreases, immune activation decreases.
Chronic "latent" asymptomatic phase:
Ongoing immune activation keeps cells over activated and therefore replicating and trafficked towards lymph nodes.
HIV preferentially infects and replicates in activated T cells. The biological situation is therefore supportive of continued HIV replication, assisted by the fact that it is an integrated provirus in many cells.
Infection of inactive cells (T and macrophage) leads to proviral reservoir. Later activation through antigen recognition (HIV or new infection) leads to HIV activation and cell death. Therefore HIV SELECTS for those cells responding to itself or new infections (a very effective immune-deficiency causing process).
Cell signalling is altered as cell cycle arrest is mediated by HIV, and progression through the cell cycle is required for successful cytokine production.
Lack of correct cytokine environment reduces T cell replacement from the thymus (hypothetical at the moment, observational evidence only).
CD8 killer T cells preferentially destroy HIV-infected CD4 T cells.
All the above leads to: selective loss of activated (useful) T cells, cytokine skewing through chronic activation, premature immune system aging (seen in many other viral infections), gradual decline in immune repertoire and eventual thymic exhaustion. This is well documented in the literature of the last 10 years, it is not my fault if they have not kept up with it.
As the available T cell repertoire (number of antigens it can recognise) is reduced to the point where HIV can no longer be controlled, the infection becomes overwhelming. It is at this stage that AIDS usually occurs."
Firstly, Nicholas Bennett does not offer any evidence, or even a single reference, in support of the above claims.
Secondly, and most importantly, according to the "HIV" theory of AIDS:
[if !vml][endif][if !vml][endif] "HIV" → T4(AID) → S → (about 30 diseases)
This means that before one gives a "mechanism by which HIV causes AIDS" evidence must exist that:
(a) all AIDS patients are infected with "HIV";
(b) "HIV" is necessary and sufficient for the decrease in T4 cells;
(c) T4 decrease is necessary and sufficient for the appearance of S.
At present there are two methods used to prove infection of AIDS patients with "HIV":
(i) the antibody test;
(ii) the viral load test
"HIV" antibody test
According to William Blattner, a well known HIV/AIDS expert, "one difficulty in assessing the specificity and sensitivity of retrovirus assays is the absence of a final 'gold standard'. In the absence of gold standards for both HTLV-I and HIV-1, the true sensitivity and specificity for the detection of viral antibodies remain imprecise".1
According to the packet insert in the Abbott HIV antibody test "At present there is no recognised standard for establishing the presence or absence of HIV-1 antibody in human blood. 2
According to Philip Mortimer, Director, Sexually Transmitted and Blood Borne Virus Laboratory, UK, "Diagnosis of HIV infection is based almost entirely on detection of antibodies to HIV, but there can be misleading cross-reactions between HIV-1 antigens and antibodies formed against other antigens, and these may lead to false-positive reactions. Thus, it may be impossible to relate an antibody response specifically to HIV-1 infection".3
This means that at present it is not possible to state what percent, if any, of the individuals who have a positive antibody test, are “HIV” infected.
The RNA "viral load" tests
According to the US Centres for Disease Control "In adults, adolescents, and children infected by other than perinatal exposure, plasma viral RNA nucleic acid tests should NOT be used in lieu of licensed HIV screening tests (e.g. repeatedly reactive enzyme immunoassay)" (emphasis in original).4
According to manufacturer Roche, "The Amplicor HIV-1 [RNA] Monitor test is not intended to be used as a screening test for HIV-1 or as a diagnostic test to confirm the presence of HIV-1 infection (Roche Diagnostic Systems, 06/96, 13-08088-001. Packet Insert).
According to Chiron- Genprobe: "The Procleix HIV-1/HCV Assay is a qualitative in vitro nucleic acid assay system for the detection of human immunodeficiency virus type 1 and/or hepatitis C virus RNA in human plasma. This assay is not intended for use as an aid in diagnosis”.5
Hence at present no reliable test exists to diagnose “HIV” infection.
(b) "HIV" AND T4 CELL DECREASE (AID)
In our rapid responses: "Is "HIV" sufficient or necessary for T4 cell decrease (AID)?" 17 August, "Is our analysis of the Zagury paper correct", 31 August, and "Causes of low CD4 counts in AIDS", it was shown that "HIV" is not sufficient or necessary for the decrease in T4 cells (AID) in AIDS patients.
(c) T4 DECREASE AND THE CLINICAL SYNDROME
The "HIV/AIDS" experts consider T4 decrease as the "hallmark" and "gold standard" of HIV infection and AIDS.6 7 Yet there is ample evidence that even a prolonged T4 decrease does not lead to the appearance of the clinical syndrome and conversely, the syndrome, that is, the AIDS indicator diseases, may appear in the presence of normal T4 cell numbers.
Low T4 cells - no AIDS indicator disease
Researchers at the University of California at Los Angeles School of Medicine found that 5% of healthy persons seeking life insurance had abnormal T4 cell 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".8
In a study on the effects of blood transfusion on patients with thalassaemia major, researchers at the Cornell University Medical Centre 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".9 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".10
In patients with Plasmodium falciparum infection Kresmer and colleagues reported “A striking decrease of CD4+ peripheral blood lymphocytes, normalizing after chemotherapy”.11 Patients who have malaria have severe immunoregulatory disturbances including decrease in T cells. A significant number of these patients also test positive for HIV but they do not develop the AID clinical syndrome, leading Vorsky 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".12
The Multicenter AIDS Cohort Study (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".13 In the same study comparing HIV positive individuals who within five years progressed to AIDS (Group A) with 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 sero-conversion than before seroconversion (2.0)". It was concluded that "sexually transmitted co-factors, pre-seroconversion and/or postseroconversion…augment (or determine) the rate of progression to AIDS".14 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.
“In both smear positive and smear negative [tuberculosis] patients there was a reduction in the total T cell and CD4 counts and an increase in the CD8 count, with a concomitant reduction in the CD4/CD8 ratio”. As with malaria, “Following successful chemotherapy, the mean CD4/CD8 ratios reverted from 0.82 to 1.57 in smear positive patients and 0.88 to 1.52 in smear negative patients, these being near normal values”.15
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".16 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".17
AIDS indicator disease in the absence of T4 cells decrease
If the cause of the AIDS indicator diseases (the syndrome) is the decreased T4 cell number then:
1. All individuals with the AIDS indicator disease should have low T4 cells;
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, night sweats, herpes zoster, herpes simplex, 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".18 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.
According to 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…".19 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".20
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 did not show improved survival compared with patients with abnormal values…the degree of suppression did not influence mortality".21 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 200 x 106/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), maramyl 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".22 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 < 200 x 106/L. However, given the well known fact the malignant neoplasms, infectious diseases and the administration of chemotherapeutic agents are themselves causes of immunosuppression,23-31 it is equally plausible 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 one study it was found that three 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/mL. However, "Within four months of symptom onset, their CD4 counts and CD4/CD8 ratios returned to normal". "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".32
That no relationship exists between opportunistic infection (OI) and T4 depletion was confirmed in another study where it was shown that "The appearance of OI and wasting syndrome was independent of T4 cells count",33 as well as other studies which show that the OI may appear in the presence of normal T4 cell numbers.34-36
As we have pointed elsewhere in this debate, (our rapid response "OKT3, OKT4 and all that", 2 September) recent data shows that the AIDS indicator diseases continue to appear even after HAART induces "immune restoration" and decrease of 'viral load" to non-detectable levels.37
The obvious conclusion is that T4 cells are not causally related to AIDS.
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Competing interests: None declared