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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( mkg_tran@yahoo.fr). 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 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 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): 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
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. 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. Fowlkes BJ, Robey EA. A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development. 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. 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. Tran MKG, Kirkiacharian S. MMTV (Mouse Mammary Tumor Virus) 3′ orf mimicks the EGF family: EGF, heregulin (c-ErbB2 ligand) , proto-oncogene Notch. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. HIV-1 Nef
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