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C.77-CD4/CD8 ratio decrease in AIDS PDF Imprimer Envoyer
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Mercredi, 18 Juillet 2012 00:32
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C.77-CD4/CD8 ratio decrease in AIDS, explained by a molecular mimicry between African HIV-1 Nef and Notch-1: Nef as a target for vaccine and NF-kB inhibitors (salicylate, resveratrol, curcumin, epigallocatechine-3-gallate).

 

Guy Mong Ky TRAN1, 2 , Adrien CAPRANI 2, Laurent GERBAUD 1

1 Auvergne University, Hospital Hotel-Dieu, Public Health Department, 63 000 Clermont-Ferrand France( Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir. ).
2 Association « Positifs », Paris Cedex 18, France( Cette adresse email est protégée contre les robots des spammeurs, vous devez activer Javascript pour la voir. ).  

Poster présenté au symposium international ISHEID 2012 Marseille

BACKGROUND

The AIDS hallmark is the simultaneous fall in CD4 and rise in CD8 T lymphocytes. Interestingly, this very pathognomonic but unexplained decrease of CD4/CD8 ratio is also characteristic of a member of the EGF family, Notch-1 function (Fowlkes BJ, 2002). Notch is defined in Drosophila development as inducing a notched wing. Calenda V (1994) found that Nef hampered drastically bone marrow progenitor cells functionality. African HIV-1 NDK strain (Spire B, 1989), which induced a fulminant AIDS killing the patient in only 15 days, decreases dramatically CD4 counts. Nef is the most abundant HIV-1 protein in infected cells (85% of mRNA). Nef is a superantigen, its action is amplified 1,000 times compared to a common antigen.

 

OBJECTIVE

We found previously Notch-1 in the 3'ORF (Open Reading Frame) or Long Terminal Repeat (LTR) of another retrovirus [Mouse Mammary Tumor Virus (MMTV)] (Tran MKG, Eurocancer, Paris 1998):

MMTV LTR 3'ORF (222-227)    PLPYTG
Notch-1 (repeat 21)         PLPYTG

We prolonged this alignment by using a chimera of Notch-1 (EGF repeats 1, 21, 22, 23, 27, 36) and Notch Drosophila (EGF repeats 22, 30):

MMTV LTR 3'ORF (213-236) PYIYRPTDA PLPYTGRY-DLNFNRW
Notch chimera            PF-YRCTNA PLPYTGRYCDLNINRW

                                                                       36 |23 |21 |1| 21 |Drosophila22|Dro30|22| 27

As Nef is located also in HIV-1 LTR, we looked for Notch-1 in Nef. 

 

 

METHODS

Amino Acid (AA) alignment [by manual alignment, associated with Basic Local Alignment Search Tool Protein (BLASTP) on mouse Notch-1] between Epidermal Growth Factor (EGF) family members and Nef (Los Alamos HIV sequences Database, 2002, 2009). The EGF repeats of the following proteins were screened : Notch-1 (mouse, rat, Xenopus) -2, -3, -4 (Int-3), Notch (Drosophila, Leishmania), Lin-12, Slit, Cripto, Delta, Heregulin α, EGF (rat, mouse, guinea pig, human, rabbit, sea urchin), uromodulin (Tamm-Horsfall), TGF α, Cowpox Vaccinia virus, Shope Fibroma virus, Plasmodium Falciparum Pfs 25, factor X (Stuart), factor IX, factor XII, ELAM 121, MEL-14, Fibrillin, LTBP, WI-1 Adhesin, PAS-6/7, Schwanomma SDGF, Epiregulin, β-cellulin, Amphiregulin, HB-EGF, TPA, Urokinase, Protein C, Protein Z, Protein S, LDLR, Thrombomodulin. As IkBα contains a Notch-like repeat (or Ankyrin repeat outside the EGF repeat), it was also included in the research list.  

 

RESULTS

Nef COOH-terminus of HIV-1 clade D African strains (from Congo Democratic Republic, Chad, Tanzania, Uganda, South Africa, Kenya), but not from other parts of the world (other clades A, B, C, E, M), was a perfect 100% molecular mimetic of Notch-1 (but not Notch-3 or other EGF family members): They shared a heptapeptide (7 AA) (Nef AA 187-191) SRLAFEH. The homology between Nef (Poon AFY, 2009) (AA 141-206) and Notch chimera (mainly Notch-1 + Notch Leishmania + Notch Drosophila + Notch-like repeat of IkBα) could be prolonged upstream and downsteam of SRLAFEH to extend 68 AA long, with 4 His (166, 171, 192, 199), 1 Cys (206) and 1 Trp (143) (very highly significant):

c77-1

Characters of Notch Droso (=Drosophila) are italicized

It included the Nef 164-LL-165 and 174-ED-175 doublets precisely implicated in CD4 down-regulation and the 155-EE-156 in β-COP recruitement (Benichou S, 1994). There is an homology of Nef with the Notch-like Ankyrin repeat of IkB-α.

Another short patch centered on a Cysteine was found between HIV-1 clade O ANT 70 and Notch-4 (1)/Notch-2 (25), as well as between Nef of SIV Syk and Notch Drosophila (14):

Nef HIV-1 clade O ANT 70            SEPCA PGVG
Notch-4 (EGF repeat 1)               EPCANGGTC
Notch-2 (EGF repeat 25)             SEPCKNGGT
Nef SIV Syk                          QPCR-GGF
Notch Drosophila (EGF repeat 14)     QPCRNRGI
Notch Drosophila (EGF repeat 14)     QPCRNRGI

 

DISCUSSION AND CONCLUSION

This opens new avenues for a vaccine targeted to Nef-Notch specific to Africa, a continent devastated by AIDS and tuberculosis (in South Africa, about 60% HIV-1 infected patients had also tuberculosis). Notch-1 contains an Ankyrin repeat/Lin-12 homologous to IκB-α, which is phosphorylated by IKKβ kinase. Aspirin, an inhibitor of IKKβ (Yin MJ, 1998), inhibits HIV-1 in vitro and has been claimed to be efficient against AIDS, but a preliminary clinical trial was stopped prematurely after appearance of some side effects (such as anemia and liver enzyme rise). We present here a biological basis for Aspirin (and Sodium Salicylate) as an anti-IKKβ kinase, and hence anti-NF-kB, namely an anti-NEF. This new mechanism of action revives this option of treatment and initiates a regain of interest on NF-kB inhibitors as anti-NEF [resveratrol of red wine, EpiGalloCatechine-3-Gallate (EGCG) of green tea, curcumin of Turmeric (associated with pepper for absorption)]. A poster is presented in this ISHEID Conference (Caprani A et al., 2012) about the efficacity and non toxicity of this anti-NEF treatment.

 

BIBLIOGRAPHY


Benichou S, Bomsel M, Bodéus M, Durand H, Douté M, Letourneur F, Camonis J, Benarous R.

Physical interaction of the HIV-1 Nef protein with beta-COP, a component of non-clathrin-coated vesicles essential for membrane traffic.
J Biol Chem 1994, 269: 30073-6.

Calenda V, Graber P, Delamarter JF, Chermann JC.

Involvement of HIV nef protein in abnormal hematopoiesis in AIDS: In vitro study on bone marrow progenitor cells.
Eur J Haematol. 1994, 52:103-7.

Fowlkes BJ, Robey EA.

A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development.
J Immunol. 2002, 169:1817-21.

Poon AFY, Swenson LC, Dong WWY, Deng W, Kosakovsky Pond SL, Brumme ZL, Mullins JI, Richman DD, Harrigan PR and Frost SDW.

PhylogeneticAnalysis of Population-Based and Deep Sequencing Data to Identify Coevolving Sites in the nef Gene of HIV-1.
Mol Biol Evol 2010, 27: 819-32.

Spire B, Sire J, Zachar V, Rey F, Barré-Sinoussi F, Galibert F, Hampe A, Chermann JC.

Nucleotide sequence of HIV1-NDK: a highly cytopathic strain of the human immunodeficiency virus.
Gene 1989, 81: 275-84.

Tran MKG, Kirkiacharian S.

MMTV (Mouse Mammary Tumor Virus) 3' orf mimicks the EGF family: EGF, heregulin (c-ErbB2 ligand) , proto-oncogene Notch.
In: Boiron M & Marty M (Eds) Eurocancer 1998. Compte Rendu du XI Congrès, 3-5 Juin 1998. John Libbey Eurotext, Paris: 177, poster 20.

Yin MJ, Yamamoto Y, Gaynor RB.

The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β.
Nature 1998, 396: 77-80.

HIV-1 Nef
(Poon AFY, Mol Biol Evol 2010, 27: 819-32).

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Mise à jour le Mercredi, 07 Novembre 2012 17:23