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C.85-Thai AIDS Vaccine RV 144: Molecular Homology Between HIV-1 Gp 120 Envelope First Conserved Regi

C.85-Thai AIDS Vaccine RV 144: Molecular Homology Between HIV-1 Gp 120 Envelope First Conserved Region C1, Which Induces IgA Antibodies Increasing AIDS Risk, And The Complement Receptor CR1

Présentation Poster au 5° congrès européen de virology Lyon Septembre 2013

Publié dans Virologie Septembre 2013, vol 17, Supplement S135

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C.86-Breast Cancer And Virus: Molecular Homology Between Human Mammary Tumor Virus 3’Orf And Scorpio

C.86-Breast Cancer And Virus: Molecular Homology Between Human Mammary Tumor Virus 3’Orf And Scorpion Toxin, A Ligand Of Voltage-Gated Sodium Na+ Channel. Omega 3, A Na+ Channel Modifier, Reduces The Risk Of Metastatic Breast Cancer.

Présentation Poster au 5° congress européen de virology (Lyon Septembre 2013) REF 017 Category: 03.Innate immunity against viruses

Publié dans Virologie Septembre 2013, vol 17, Supplement S123

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C.84-AIDS Vaccine Thai RV 144 Correlate Of Protection: Envelope gp120 V2 Loop, Which Induces Protect

C.84-AIDS Vaccine Thai RV 144 Correlate Of Protection: Envelope gp120 V2 Loop, Which Induces Protective Neutralizing IgG Antibodies, Is A Marine Conus Mu-Conotoxin Binding To The Voltage-Gated Na+ Sodium Channel

Présentation Poster au 5°congrès européen de virologie ( Lyon, Septembre 2013)

REF 058         Category: 04. Adaptive immunity and Vaccines

Publié dans Virologie Septembre 2013, vol 17, Supplement S 134

 

Thai RV 144 vaccine efficacy is 31%; protective IgG target the gp120 V1-V2 loops. We analyse the V2 loop (Zolla-Pazner S, 2013) by Amino Acid (AA) sequences comparison by Basic Local Analysis Search Tool Protein (BLASTP) with visual search and three-dimensional (3D) structures of conotoxin (Xue T, 2003) and spider Atrax atracotoxin (Pallaghy PK, 1997). The 2 Thai vaccine strains V2 loops were screened on toxins binding to the voltage-gated Na  channel (NaCh). Result: 1) 3 mu-conotoxin active site AAs (K13, Q14, K16) (Conus Geographicus, Kinoshitai, Striatus, Betulinus chimera) (Ekberg J, 2008) are found in the Thai V2 loop (V172 crucial):

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2) The vaccine MN strain V2 loop mimics the scorpion toxin NH2-terminus active site 1-KKEGY-5 (Kharrat R, 1989); its deletion abolishes the toxicity (El Ayeb M, 1986). Interestingly antibodies against scorpion toxin NH2-terminus 1-KKEGY-5 induce broad cross-reactive protection (Devaux C, 1996). The toxin precursor (Cn II-13, AaH, Bot IX chimera) (Possani LD, 2000) is included.

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3) V2/V3 loops of HIV-2/SIV PBJ14 (fatal AIDS) were 3D superimposed on spider Atratoxin (Atx)/versustoxin, 2 NaCh ligands. Atrax Robustus is a very dangerous spider from Australia.

V2 loop YxxxWYxxDxxC is conserved in HIV-2.

V3 loop AA sequence is SGLVFH:

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CONCLUSION

The scorpion venom concept of AIDS (Tran GMK, 1989, 1993, 1997) is confirmed by the homology between the Thai V2 loop and mu-conotoxin, a NaCh ligand. Omega-3, a NaCh modifier, is efficient in AIDS (Caprani A, 2012). AIDS vaccine should target V2/V3 loop, and avoid mitigating and deleterious IgA directed against the envelope first conserved region C1 (Haynes BF, 2012) (Tran GMK, Eur Conf Virol 2013, Lyon).

An AIDS therapeutic vaccine (as was the case for Pasteur anti-rabies vaccine) would be more rapid to develop, step by step, than a classical prophylactic vaccine: The rapidity of a therapeutic vaccine is calculated in months, whereas for a prophylactic vaccine, each trial would take about a dozen of years. The same therapeutic vaccine, when finally successful, can be then converted in a prophylactic vaccine (following the anti-rabies vaccine example).

The scorpion model of AIDS means that there must at least 6 or 7 different AIDS vaccines, as numerous as the number of different geographical species of scorpions. A mannose-based vaccine must be added to the proteins.

 

BIBLIOGRAPHY

 

Caprani A , Tran GMK and Roudiere L. Use of new targets (D-Mannose receptor, sodium channel voltage dependent) in a new effective, low cost HAART. Validation with the presentation of a clinical case. 17th Int Symp HIV Emerging Inf Dis (ISHEID) 2012, Marseille. Retrovirology 2012, 9 Suppl 1: P13.  Devaux C, Fourquet P, Granier C. A conserved sequence region of scorpion toxins rendered immunogenic induces broadly cross-reactive, neutralizing antibodies. Eur J Biochem. 1996, 242: 727-35. Ekberg J, Craik DJ, Adams DJ. Conotoxin modulation of voltage-gated sodium channels. Int J Biochem Cell Biol. 2008, 40: 2363-8. Review. El Ayeb M, Darbon H, Bahraoui EM, Vargas O, Rochat H. Differential effects of defined chemical modifications on antigenic and pharmacological activities of scorpion alpha and beta toxins. Eur J Biochem. 1986, 155: 289-94. Haynes BF, Gilbert PB, McElrath MJ et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012, 366: 1275-86. Kharrat R, Darbon H, Rochat H, Granier C. Structure/activity relationships of scorpion alpha-toxins. Multiple residues contribute to the interaction with receptors. Eur J Biochem. 1989, 181: 381-90. Pallaghy PK, Alewood D, Alewood PF, Norton RS. Solution structure of robustoxin, the lethal neurotoxin from the funnel-web spider Atrax robustus. FEBS Lett. 1997, 419: 191-6. Possani LD, Merino E, Corona M, Bolivar F, Becerril B. Peptides and genes coding for scorpion toxins that affect ion-channels. Biochimie. 2000, 82: 861-8. Review.  Tran MKG. Homology of HIV 1 gp110 with venoms (scorpion, sea anemone; cobra cytotoxin) whose receptors are ionic channels (Na+ acetylcholine regulated; Ca++). XIX Congress Pediatrics, Paris Jul 1989. Poster M-24. Tran MKG. HIV1 envelope V3 loop mimics scorpion and spider neurotoxins, whose receptor, the Na+ sodium channel, is the target of Tacrine (THA, TetraHydroAminoAcridine). IXth Int. Conf. AIDS, Berlin Jun 1993. Abstr PO-A01-0022. Tran GMK. The scorpion venom model of Aids: Mimicry between anti-V3 loop antibody and the sodium channel the target of Tacrine: A possible vaccine. Europ Aids Clin Soc (EACS), 1997: Abstract 475.  Xue T, Ennis IL, Sato K, French RJ, Li RA. Novel interactions identified between micro-Conotoxin and the Na+ channel domain I P-loop: implications for toxin-pore binding geometry. Biophys J. 2003, 85: 2299-310.  Zolla-Pazner S, deCamp AC, Cardozo T et al.  Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLoS One. 2013, 8(1): e53629. doi: 10.1371/journal.pone.0053629.

Acknowledgements: Positifs Association.

 

 

 

 

 

 

 

 


 
C.83-BASES MOLECULAIRES DES « ALICAMENTS » DU CANCER DE LA PROSTATE : BLOCAGE DE NF-KB, STIMULATION

C.83-BASES MOLECULAIRES DES « ALICAMENTS » DU CANCER DE LA PROSTATE : BLOCAGE DE NF-KB, STIMULATION DE P53 ET APOPTOSE MITOCHONDRIALE

Poster présenté à la journée  de l’ARTP du 20 novembre 2013

 

Introduction : Une alimentation anti-cancer de la prostate (KP), basée sur les mécanismes d’action moléculaires des « alicaments », renforce l’efficacité du traitement classique.

 

Methodes : Revue de la littérature, livres (David Servan-Schreiber (2010), David Khayat (2010), Denis Gingras/Richard Beliveau (2005).

 

Resultats : Le régime alimentaire du KP comprend : Thé vert, resvératrol, curcuma, jus de grenade, graines de lin, soja, sélénium, tomates cuites, algue brune, choux, alliacés, vitamine D3, café, baies de Goji, huile d’argan et sport.

Le thé vert (EGCG) inhibe NF-kB et stimule p53, est actif en clinique.

Le vin rouge (resvératrol) (1 verre/j) entraine une baisse de 40% du cancer. Il inhibe NF-kB, stimule p53, induit une apoptose et améliore la réparation des gènes.

Le curcuma (associé au poivre): L’incidence du KP est de 5/100 000 en Inde (consommation du curcuma), contre 104/100 000 aux USA (pas de consommation); la curcumine inhibe NF-kB et stimule p53.

Le jus de grenade divise par 3 la vitesse de propagation du cancer opéré en rechute.

Les graines de lin moulues ralentissent la croissance des tumeurs de 40%.

La génistéine du soja retarde la progression après traitement local, bloque la division  et stimule l’apoptose.

Le sélénium diminue de moitié les cancers (17 versus 35) sur 974 personnes.

La tomate cuite (lycopène) diminue le risque de 30%.

La fucoxanthine (algue brune) inhibe la croissance des cellules cancéreuses. Eviter les algues japonaises radio-actives.

Les crucifères [choux (sulforaphane)] sont plus efficaces que la tomate.

Les alliacés [ail (allicine, diallyl sulfide)] > 10g/j entrainent 50% moins de cancer qu’à  < 2g/j.

La vitamine D3 (2 000 UI/j) fait régresser le PSA.

Le café à fortes doses diminue de 60% le risque de KP mortel.

Les baies de Goji (Lycium Barbarum) induisent l’apoptose et inhibent la croissance d’une xénogreffe chez la souris.

L’huile d’argan (polyphénols) inhibe les cultures cellulaires de KP.

 

Conclusion: Les « alicaments » sont non toxiques, ont montré une réelle efficacité dans des études cliniques (vin rouge, jus de grenade, graines de lin, ail, soja, sélénium, tomate, café à fortes doses même décaféiné). Le mécanisme (pour le thé vert, le curcuma, le café et le vin rouge) est le blocage de NF-kB, la stimulation de p53 et l’induction de l’apoptose mitochondriale.

 

 

 

 
C.82bis- Therapeutic Protocol defended by the "POSITIFS" Association. Replacement of HAART by a low

C.82bis- Therapeutic Protocol defended by the "POSITIFS" Association.
Replacement of HAART by a low toxicity treatment involving new targets of HIV, in patients intolerant to protease inhibitors or resistant to anti-integrase or seeking a less toxic treatment


Introduction

Although the main objective of zero or undetectable viral load is achieved by a treatment based on protease inhibitors and / or anti-integrase, demonstrating their effectiveness, these treatments are still imperfect because of their toxicity and side effects resulting from these two options:
1) Lipodystrophy, for anti-proteases, threatening the long-term development of cardiovascular complications and increased mortality risk significantly, or
2) ineffectiveness of anti-integrase
and forcing them to ascertain whether there is another possible treatment option, but that it must be found, in the case of former patients who have exhausted all the "arms" of the armamentarium of Pharmaceutical Companies.

The absence of alternative therapeutic option in these two impasses is especially urgent the discovery of new efficient and especially non-toxic treatments that can take over in case of major side effects (lipodystrophy). Ideally, a completely harmless armamentorium, since the patient must undergo treatment for life, and who nonetheless remain 100% effective, that is to say capable of maintaining an undetectable viral load: An ideal treatment.

 


Basis of the proposal of clinical research protocol:

A) Biological Requirements

1) work of Bandivdekar  on Mannose receptor and Tran GMK work on sodium channel voltage-dependent, both co-receptors for HIV non-target date by Pharmaceutical Companies.
The mechanism of action at the molecular biology is blocking the virus  at the entry into the cell, by targeting these two new receptors (different from CD4, CCR5 and CXCR4):
a) The mannose receptor and
b) The receptor whose ligands  are gp120, gp41, Nef and part scorpion-like protease (Tran GMK, work submitted, not yet published), this receptor is the sodium channel voltage-dependent or receptor long scorpion venom toxin.
Blocking the sodium channel was already successfully completed and published (Fredj and Dietlin, society Newpharm) in 1989, clinically with Tacrine (tetrahydroaminoacridine or THA), which acts specifically on the sodium channel (Schauf and Sattin), but hepatotoxicity of Tacrine had prevented the increase in dose until the optimal dose (ie beyond 150 mg / day), resulting in a modest effect if real and an obligation to properly navigate the pitfalls of hypertransaminémia. The first test with Tacrine on a series of only a few patients had used doses too low (test of English Mike Youle) and was quickly abandoned.
This concept of the scorpion venom toxin model was developed from 1988-1989 by Tran MKG and also simultaneously by Werner in Germany (published in AIDS, see Garry RF editorial citing, with my permission, my alignments) . The European AIDS Clinical Society (EACS) was also elected as a member of its Scientific Council for about 10 years, Tran GMK for his decisive contribution to this discovery while to actually innovative, but considered a little "magic "for the time. It must be said that at the time, astrologers claimed that the AIDS epidemic had become following the merger of Pluto (planet of Scorpio) Earth (see Daily Doctor). They also predicted that the epidemic would decline gradually as and when the distance of Pluto, which ... has been achieved.
This closed unscientific astrological parenthesis, it is the work of very pure molecular biology have revealed very highly significant molecular mimicry between the scorpion toxin and HIV-1. This is not an astrological demonstration based on "influence" of Pluto on Earth.
A poisonous toxin is a molecular mimic virus has already demonstrated in the case of rabies and snake neurotoxin Naja (Lentz, Science). There is nothing there astrological, it's totally simple scientific toxinology. Still regarding rabies, we confirmed the presence of a second snake neurotoxin at residue Arg 333 (Tran GMK, unpublished), thus explaining the two clinical forms of rabies.
 
Confirmation of the concept of scorpion toxin by the Thai RV144 vaccine

This vaccine provides a low final protection  of  about 30%, but mainly
evident at the beginning of the test (probably because HIV-1 has not yet had time to mutate): Statistically, the 30% protection was questioned later, however, the fact remains that the difference is very significant at the beginning of the trial, with significantly more than 30% protection.

Recently, therefore, there has been an unexpected confirmation of the concept of voltage-gated sodium channel and toxins binding to the channel, the scorpion toxin: In fact, the first anti-AIDS vaccine in the world have had an efficiency (. Rerks-Ngarm S et al, NEJM, 2009) after more than a hundred failures, the recent Thai RV144 vaccine is - we now know - by an immunological mechanism targeting precisely, and only, the V1 and V2 loops of the gp120 of the envelope of HIV-1;

The correlate of vaccine protection is humoral: neutralizing antibody loops V1 and V2.

But these two hypervariable loops are well known by TRAN GMK, who had studied under the scorpion toxin, as well as the V3 loop (TRAN GMK): This work is not yet published, but V1 and V2 are also cone sea toxins (for the Thai vaccine strain) and scorpion (for the MN strain). This discovery was made in 1994 for the MN strain, but its meaning at the time was only to reinforce the concept of scorpion toxin obtained with mimicry between V3 and scorpion venom of Androctonus Australis Hector Aah II that Marc Girard had confirmed on the animal discovering  that anti-V3 antibodies protected chimpanzees, though specific type only.
Now, the success of the RV144 Thai vaccine, UNDISPUTED AT THE BEGINNING, however modest or no in the end, allows to suggest that the protection afforded to a clear mechanism: Neutralization of V1 and V2 loops of antibodies. One knows the type of immunity: Humoral alone, without the intervention of cellular immunity, especially the target antibodies are precisely known: the V1 and V2 loops of the gp120 envelope of HIV-1. Therefore, as these loops are cone sea and scorpion toxins, that means they bind to the voltage-gated sodium channel that is the receptor of two toxins, both the toxin of the cone and the toxin long  of the scorpion.
In short, to sum up, one of the "correlates of protection", so mysterious and so sought in vain for decades, in the anti-AIDS vaccine is an antibody binding to the hypervariable loops V1 and V2 gp120, and these two loops are 
toxins cone sea (for the Thai vaccine strain) and scorpion (for the MN strain) binding to the sodium channel. This channel is the therapeutic target of omega-3. (Isbilan Banu 2006 Marchioli R 2002 study Gissi).


Give omega 3  leads to inhibit V1, V2 and V3 loops of gp120 and gp41 of HIV-1.

2) Work on Resveratrol
Zhang HS (anti-Tat activity) of
Heredia (synergy with nucleoside analogues) and
Tran GMK (anti-Nef activity, results presented at the 17th Post ISHEID Marseille  and on www.positifs.org C77). Nef acts on the CD4 count, the CD4/CD8 ratio and as Nef  represents 85% of the mRNA of a person infected with HIV-1 cell, on the other hand is a "superantigen" (which amplifies 10 000 times the action of the virus), inhibit Nef will be crucial to overcome AIDS.
Anti-Nuclear Factor kappa B activity (NFkB) of resveratrol
suggests it will have a preventive effect on the occurrence of cancer, which is a sword of Damocles over the long term AIDS patients. Among other anti-NF- kB there is turmeric, Epi gallo catechin-3-gallate (EGCG) in green tea. So these are anti-cancer drugs, but also simultaneously anti-Nef. Their use is a double benefit for the patient: Prevent HIV-1 to act, particularly increasing the rate of CD4 (since Nef decreases the rate) and prevent the occurrence of cancer.
This is not mere speculation of a molecular biologist locked in his ivory tower, but a clinic is authenticated by clinical studies published in the international literature: The anti-NF-kB molecules such as green tea ( EGCG) have been studied in lung cancer of smokers in January 2009 on 700 smokers Coronado (USA): EGCG reduces the risk 15 times. Similarly, the fungi associated with green tea reduced by 85% the risk of breast cancer in a 2009 study involving 1,000women.
About lung cancer, AIDS as it affects the rest of the population, and therefore the interest of EGCG is major. This suggests that we should study the incidence of cancer as "end point" in AIDS patients taking anti-NF-kB, to determine whether a cancer preventive effect.


IN SUMMARY

The attack HIV-1 virus is a crossfire (as in defenses Vauban fortifications): The abuser HIV-1 is subjected to heavy fire from four different directions simultaneously attack is:
-gp120(theD-Mannose)
-Nef and Tat (by resveratrol)
-Reverse Transcriptase (with 3TC) and
-envelope glycoprotein (gp120, gp41) (for the omega-3).
Note that the Omegaven is an IV infusion of omega-3, used in parenteral lipid diet.


Clinical confirmation


1) In addition to the former work Fredj G and Dietlin in 1989 on the inhibition at the sodium channel (the Tacrine)


2) Results of one of us (Adrien Caprani) with combination therapy (3TC, Resveratrol, D-Mannose, Omacor) Poster presented in the 17th ISHEID Marseille (C75 and C75bis on www.postifs.org) . This treatment alone can maintain an undetectable viral load for 10 months, no significant changes in CD4 (504 + / -15 vs. 492 + / -30) *, with a slight
increased CD4/CD8 ratio (0.61 vs. 0.50), normalization of activated T (7% vs. 15%) and a significant increase in natural killer (NK) cells (24% v 8%).

* NB The last digit of CD4 is very favorable, with a climb of about 700 to ~ 550-600 (August 2012). The "stall" ascending was not known and had not been published at the time of ISHEID Conference in Marseille.
2) The objective, given the upward momentum of CD4 would get 300 more CD4 or CD4 in 1000, or normal count, that is to say, the complete recovery of the patient, improving the current treatment in August 2012 by several complementary therapies;
A more powerful protocol theoretically include, in addition to four other (3TC + Resveratrol + D-Mannose + Omega-3) harmless nutraceuticals part somehow the daily diet.

3) 4 nutraceuticals are possible:
- Green tea (EGCG), anti-NF-kB
- A spice, turmeric (anti-integrase), which is not properly absorbed  if not associated with black pepper (WARNING!)
- Traditional African Herbal Medicine: Herbal Alternanthera pungens (Djohan YF, 2009, Ann Biol Clin 67: 563-8)
- TRIPHALA MIX (containing Arura) Tibeto-Ayurvedic (TRAN GMK, unpublished)

A fifth-requires prior virologic study to test SPECIFICALLY against HIV-1: The grapefruit seed extract (about 800 active pathogens: viruses, bacteria and fungi).
One-sixth candidate is sodium salicylate, anti-NF-kB, which inhibits HIV-1. A derivative of the second generation was recently synthesized in the U.S. to avoid side effects.


CRITERIA FOR INCLUSION:


Patients intolerant to protease inhibitors and / or non-responders to anti-integrase.
Patients responding to standard treatment with undetectable viral load.

Absence of the 184 mutation in reverse transcriptase (3TC resistance mutation)

Number of participants: 300 in three groups of 100 patients

Test duration: 1 year

Treatment groups:
First and second groups: 100 patients intolerant to protease inhibitors (group 1) and
100 patients intolerant / RESISTANT anti-integrase (second group)

Combined therapy
3TC (150 mg 2/day in 2 doses) +
Resveratrol | Biotivia Transmax TR (500 mg 2/day in 2 doses)]
D-Mannose (3g/day in 3 doses)
Omega-3 [Omacor (2g/day in 2 doses)]
for two types of patients

3rd group: conventional treatment with drugs first line or second line until an undetectable viral load, and when it is achieved, immediate replacement with 3TC + Resveratrol + D-Mannose + Omacor (n = 100 patients responding to standard therapy with undetectable viral load) to prevent the occurrence of side effects.


Patient monitoring
CD4 and CD4/CD8 ratio, viral load + standard blood parameters at 1 month, 3 months, 6 months, 12 months
Activated T cells and natural killer (NK) at 0, 6 months, 12 months

Evaluation of the protocol and expected results
for the-3 treatment groups:

Group 1: For patients unresponsive to standard treatments, maintaining undetectable viral load and maintaining or increasing CD4
Groups 2 and 3: For patients intolerant to protease inhibitors and / or anti-integrase return to undetectable and increased CD4.
Disappearance of lipodystrophy in group 2 (after stopping protease inhibitors)
Absence or decrease the severity of the cancer or cancer risk in the 3 groups.



Protocol prepared jointly by:

- Guy Mong Ky TRAN (European AIDS Clinical Society (EACS) Scientific Council Member, and University of Auvergne, Department of Public Health (Pr Laurent GERBAUD) Hôtel-Dieu Hospital of Clermont-Ferrand.
- Adrien CAPRANI (CNRS, Paris), EACS and IAS member

 

 

 

 

 


 


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