A critical analysis of the pharmacology of AZT and its use in AIDS.

The triphosphorylated form of the nucleoside analogue 3'-azido-3'-deoxythymidine (Zidovudine, AZT) is claimed to interrupt the HIV replication cycle by a selective inhibition of viral reverse transcriptase, thereby preventing the formation of new proviral DNA in permissive, uninfected cells. Given that initial HIV infection of an individual instigates abundant HIV replication from inception until death, and that the life of infected T-cells is only several days, the administration of AZT should lead both in vitro and in vivo (i) to decreased formation of proviral DNA; and thus (ii) to decreased frequencies of 'HIV isolation' (detection of p24 or reverse transcription or both) in stimulated cultures/cocultures of T-cells from seropositive individuals; (iii) to decreased synthesis of HIV p24 and RNA ('antigenaemia', 'plasma viraemia', 'viral load') ultimately resulting in low or absent levels of all three parameters; and (iv) to a perfect and direct correlation between all these parameters. A critical analysis of the presently available data shows that no such evidence exists, an outcome not unexpected given the pharmacological data on AZT. HIV experts all agree that only the triphosphorylated form of AZT (AZTTP) and not the unphosphorylated form administered to patients, nor its mono- or diphosphate, is the active agent. Furthermore, the mechanism of action is the ability of AZTTP to halt the formation of HIV-DNA (chain termination). However, although this claim was posited from the outset, AZT underwent clinical trials and was introduced as a specific anti-HIV drug many years before there were any data proving that the cells of patients are able to triphosphorylate the parent compound to a level considered sufficient for its putative pharmacological action. Notwithstanding, from the evidence published since 1991 it has become apparent that no such phosphorylation takes place and thus AZT cannot possess an anti-HIV effect. However, the scientific literature does elucidate: (i) a number of biochemical mechanisms which predicate the likelihood of widespread, serious toxicity from use of this drug; (ii) in vitro data proving that AZT has significant antibacterial and antiviral properties which confound interpretation of its effects when administered to patients. Based on all these data it is difficult if not impossible to explain why AZT was introduced and still remains the most widely recommended and used anti-HIV drug.

HIV antibodies: further questions and a plea for clarification.

The existence of specific antibody/protein reactions is the crucial assumption underlying proof of HIV isolation, proof of HIV infection and the causative role of HIV in AIDS. However, since 1. antibodies which react with the 'HIV' proteins arise following allogenic stimuli in non-HIV-infected animals and humans, as well as in mice and humans with autoimmune disorders; antibodies to antigens from both mycobacteria and yeasts cross-react with HIV env and gag proteins; 2. individuals belonging to the AIDS risk groups are subjected to allogenic stimuli and have high levels of autoimmune antibodies, while the vast majority of patients in the AIDS risk groups are infected with either or both mycobacteria or yeasts; the evidence for the existence of HIV and its putative role in AIDS must be reappraised.

Factor VIII, HIV and AIDS in haemophiliacs: an analysis of their relationship.

In this review, the association between the Acquired Immune Deficiency Syndrome (AIDS) and haemophilia has been carefully examined, especially the data that have been interpreted as indicating transmission of the human immunodeficiency virus (HIV) to the recipients of purportedly contaminated factor VIII preparations. In our view, the published data do not prove the hypothesis that such transmission occurs, and therefore HIV cannot account for AIDS in haemophiliacs.

A critical analysis of the HIV-T4-cell-AIDS hypothesis.

The data generally accepted as proving the HIV theory of AIDS, HIV cytopathy, destruction of T4 lymphocytes, and the relationship between T4 cells, HIV and the acquired immune deficiency clinical syndrome are critically evaluated. It is concluded these data do not prove that HIV preferentially destroys T4 cells or has any cytopathic effects, nor do they demonstrate that T4 cells are preferentially destroyed in AIDS patients, or that T4 cell destruction and HIV are either necessary or sufficient prerequisites for the development of the clinical syndrome.

AIDS in Africa: distinguishing fact and fiction.

The data widely purporting to show the existence and heterosexual transmission in Africa of a new syndrome caused by a retrovirus which induces immune deficiency are critically evaluated. It is concluded that both acquired immune deficiency (AID) and the symptoms and diseases which constitute the clinical syndrome (S) are of long standing in Africa, affect both sexes equally and are caused directly and indirectly by factors other than human immunodeficiency virus (HIV). Seropositivity to HIV in Africans usually represents no more than cross-reactivity caused by an abundance of antibodies induced by the numerous infectious and parasitic diseases which are endemic in Africa. The apparently high prevalence of 'AIDS' and 'HIV' seropositives is therefore not surprising and is not proof of heterosexual transmission of either HIV or AIDS.

Is a positive western blot proof of HIV infection?

It is currently accepted that a positive Western blot (WB) HIV antibody test is synonymous with HIV infection and the attendant risk of developing AIDS. In this communication we present a critical evaluation of the presently available data on HIV isolation and antibody testing. This evidence indicates that: (1) the antibody tests are not standardized; (2) the antibody tests are not reproducible; (3) the WB proteins (bands) which are considered to be encoded by the HIV genome and to be specific to HIV may not be encoded by the HIV genome and may in fact represent normal cellular proteins; (4) even if the proteins are specific to HIV, because no gold standard has been used to determine specificity, a positive WB may represent nothing more than cross-reactivity with non-HIV antibodies present in AIDS patients and those at risk. We conclude that the use of antibody tests as a diagnostic and epidemiological tool for HIV infection needs to be reappraised.

Kaposi's sarcoma and HIV.

Recently published informed debate affords strong indication that in patients with the Acquired Immune Deficiency Syndrome, HIV cannot, directly or indirectly, be the cause of Kaposi's sarcoma. This paper provides reasons for disallowing a current alternative theory that Kaposi's sarcoma is due to an unidentified sexually transmitted infectious agent and proposes instead that Kaposi's sarcoma is the result of prolonged and repeated exposure to nitrites and/or semen. If this alternative hypothesis is strengthened by confirmation of its predictions then the relationship of HIV to Kaposi's sarcoma, one of the principal AIDS-associated diseases, becomes somewhat remote. This may facilitate a shift of emphasis and encourage the development of alternative therapies.

Importance of the redox state in vasoconstriction induced by adrenaline and serotonin.

The actin myosin system and the redox state have been implicated in a number of cellular functions and in many pathological conditions. To study the predictions of a new redox theory of actin-myosin interaction we examined the relationship between the redox state and vasoconstriction of rat aorta and dog basilar artery by adrenaline and serotonin. The results show that the contraction induced by these physiological agents can be inhibited and reversed by reducing agents.

Reappraisal of AIDS--is the oxidation induced by the risk factors the primary cause?

The emergence of AIDS as a recognizable disease, its epidemiology, the clinical and laboratory data and the way in which they have been interpreted to deduce the currently acceptable hypothesis of its aetiology and mechanism of transmission are critically examined. There is no compelling reason for preferring the viral hypothesis of AIDS to one based on the activity of oxidizing agents. In fact, the latter is to be preferred, since unlike the viral hypothesis it leads to possible methods of prevention and treatment using currently available therapeutic substances.

Evidence that the redox state has a role in muscular contraction and relaxation.

The present work reports that simple oxidizing agents are capable of inducing isotonic contraction of rat aorta in vitro, and that the concentration of agent required depends on its oxidizing potential. Conversely a reducing agent will reverse a muscular contraction induced by oxidizing agents.