martedì 10 aprile 2012

The Weak Link Between GcMAF and HIV infection. A Broken Arrow in the AIDS Denialists’ Quiver.


Guido Poli, director of the AIDS Immunopathogenesis Unit at the San Raffaele Hospital and Professor of Pathology, School of Medicine, of the Vita-Salute San Raffaele University in Milano, wrote a paper for SIMIT (Società Italiana di Malattie Infettive eTropicali) on GcMAF, HIV infection and Professor Ruggiero’s team research.

The paper is accessible only to the physicians members of SIMIT, but Professor Poli gave us the authorization to spread it even to non-infectious diseases experts.


The Weak Link Between GcMAF and HIV infection. A Broken Arrow in the AIDS Denialists’ Quiver.

Guido Poli

AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy


At the recent ICAR meeting held in Florence, March 2011, a poster presented by Gabriele Morucci and Tiziana Punzi of the University of Florence, Italy, discussing “Effect of Cadmium and Gc-Macrophage Activating Factor (Gc-MAF) on Intracellular HIV Targets in Normal and Transformed Human Breast Cells” has raised the voice and enthusiasm of so-called AIDS denialists, i.e. individuals not acknowledging the etiology of AIDS in the infection by the human immunodeficiency virus (HIV) 1. Not as much for the scientific content of their poster, as later discussed,but for incorporating in their conclusions the sentence: “Our data….provide experimental evidence for the words “Our immune system will get rid of the virus within a few weeks, if you have a good immune system”, thus reversing the longassumed cause-effect relationship between HIV and AIDS.” The poster is now displayed in the web site of the Gc-MAF producing company in support of their market to use this molecule to cure “cancer, AIDS and immune diseases”. Here we will revise what is known on Gc-MAF effects on HIV infection in vitro and in vivo.


The first consideration is that in the era of recombinant technology that has allowed the sequencing of the human genome it is unusual that a “relevant” biological activity described in 1987 (by the same group now claiming its efficacy against HIV infection 2) has not lead to identification of a specific gene and related protein. The term “MAF” was commonly used in the ‘70s and it has been essentially abandoned in the field after the demonstration of its identity with interferon-γ (IFN-γ), indeed a main “macrophage activating factor” 3. A paper identifying a MAF distinct from IFN- γ was published in 1988 4, but did not have follow-up. Of course, IFN-γ is not the only “macrophage activating factor” since this function can be exerted by several cytokines, chemokines and factors of non-proteic nature such as prostaglandins and leukotriens.

Second, the “key reference” paper cited by the authors in their poster was published in 2009 5. Almost all references related to GcMAF cited in the paper are self-referred (i.e. they refer to publications by the same group of investigators), a very suspicious indicator of the relevance of the “discoveries” described in the papers. A more technical analysis of their published data reveal the adoption of questionable methodologies to approach a monumental issue such as “viral eradication”, including the use of a cell line-based culture method to determine “the viral load in patient plasma” rather then sensitive PCR-based methods (or equivalents); also when RT-PCR was adopted its cut-off was 400 copies/ml, a standard clearly obsolete in comparison to the common standard of 50 copies or less in use by several years. The implication that “administration of GcMAF normalized the levels of Nagalase activity (an enzyme that, according to the authors, deglycosylate the MAF precursor leading to inactivation of MAF and it is upregulated by HIV infection and “it is an intrinsic component of the envelope protein gp120”) to those of healthy controls, indicating eradication of HIV-infection” is so evidently unproven that the reviewers and the Editor of the Journal of Medical Virology (IF: 2,47) should have required its elimination for the broad implication that such a sentence could have implied. Indeed, the same sentence has been indeed incorporated in the Introduction of the poster by Morucci and Punzi: “Thus, it was demonstrated that GcMAF eradicates HIV infection in asymptomatic HIV-infected patients 5, and here we report for the first time its effects in full-blown AIDS patients (BOX 1).”

This poster Box 1 summarizes the features of two AIDS patients that have spontaneously decided to assume GcMAF. Case report 1 describes the case of a patient resistant to “conventional ARV” (not specified) who experienced a gain in CD4+ cell counts (from 40 to 298 cells/ml – likely meaning “μl”…) and reduction of viremia from 160,000 to 2,343 copies/ml after 10 weeks of suspension of the conventional ARV therapy and assumption of GcMAF by intramuscular injection with improvement of general conditions including peripheral neuropathic pain and limb stiffness. The second case report describes the events occurring in another AIDS patient who, after the third injection of GcMAF after HAART suspension experienced significant systemic inflammatory symptoms following GcMAF injection (flushes, diffused muscle pain, high fever, headache, etc.) relieved by assumption of an antiinflammatory agent. The only additional information provided is that “ever since the patient reports constant improving of her general conditions.” for which the authors astonishingly conclude that “These side effects, although unwelcomed, appear to demonstrate that GcMAF actually induces immune system reconstitution.” Clearly, these two cases do not allow any inference on the efficacy of GcMAF on HIV replication in vivo, since the amelioration of general conditions, the improvement of CD4+ cell counts and reduction (in any case, not eradication!) of viremia in a multidrug experienced patients, although of interest, could be the result of multiple variables not reported in the summary. The second case description strikes for lack of clinical data (viremia? CD4 cell counts?) and raises the concern that GcMAF could induce systemic inflammatory reactions and not “immune reconstitution effects” as incomprehensibly interpreted by the authors. The remainder of the poster describes activating/differentiating effects on a breast cancer cell line (MCF-7) and on a mononuclear phagocyte cell line (MonoMac 6) in response to GcMAF, results that are clearly not related to HIV infection and to the final claim of the authors.

In conclusion, the anecdotal use of GcMAF in HIV infected individuals does not gain any scientific support by the present poster and should not be encouraged by the medical community. On the contrary, the information, based on the present report, that GcMAF may induce a systemic inflammatory syndrome should be communicated to the medical community to further discourage its “experimental” use in HIV infected individuals. 

This conclusion is in line with the comment of the journal Medical Hypothesis that decided to withdraw a paper by the team to which the authors of this poster belong: “This Article-in-Press has been permanently withdrawn. The editorial policy of Medical Hypotheses makes it clear that the journal considers "radical, speculative, and non-mainstream scientific ideas", and articles will only be acceptable if they are "coherent and clearly expressed." However, we received serious expressions of concern about the quality of this article. Given these important signals of concern, we commissioned an external expert panel to investigate the circumstances in which this article came to be published online. The panel recommended that the article should be externally peer-reviewed. Following a peer-review process managed by The Lancet editorial team, all five external reviewers recommended rejection, as a result of which the expert panel recommended permanent withdrawal. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. 1


References

1. Ruggiero M, Galletti MP, Pacini S, Punzi T, Morucci G, Gulisano M. WITHDRAWN: Aids denialism at the ministry of health. Med Hypotheses. 2009.
2. Yamamoto N, Ngwenya BZ. Activation of mouse peritoneal macrophages by lysophospholipids and ether derivatives of neutral lipids and phospholipids. Cancer Res. 1987;47:2008-2013.
3. Billiau A, Matthys P. Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev. 2009;20:97-113.
4. Jones MP, Gunapala DE, Matutes E, Catovsky D, Coates AR. A novel human macrophage-activating factor: distinction from interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GMCSF). Cell Immunol. 1988;113:361-375.
5. Yamamoto N, Ushijima N, Koga Y. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009;81:16-26.




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