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Poster présenté par l’associaton Positifs
Multiple sclerosis (MS) and Epstein-Barr virus (EBV): Molecular homology between Myelin
TRAN M.K.G. 1*, Caprani A. * 1 Public Health Department (Room 535, Bio-informatics; and Occupational Medicine Institute (Pr Chamoux A.) CHUR Gabriel Montpied, 63 000 Clermont-Ferrand, France. E-mail: mkg_tran@yahoo.fr
INTRODUCTION Epstein-Barr Virus (EBV) infections when occuring late in adults (infectious mononucleosis) enhanced 20 fold the relative risk to contract MS (Review in: Ascherio A, Ann Neurol 2007). Oligoclonal IgG antibodies (or OCB= Oligoclonal Bands) in cerebrospinal fluid, a hallmark of Multiple Sclerosis, are directed against EBV EBNA-1 repeat amino acid sequence Alanine-Glycine-Alanine-Glycine-Glycine-Alanine AGAGG (Cepok S, 2005). Human T-cell leukaemia virus-1 (HTLV- 1) infects some 20 millions individuals worldwide; only 2-5% will develop a chronic encephalomyelopathy, HTLV-1 associated Myelopathy / Tropical Spastic Paraparesis (HAM/TSP) (Beby-Defaux A., 1999). HTLV-2 has also been found in TSP among Amerindiens, with a periventricular demyelinisation (Beilke M.A., 2005; Araujo A., 2004). HAM/TSP possibly mimics MS (Reddy E.P., 1989). Five viruses were found in MS: EBV: Carriers of the HLA DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS; The relative risk of MS among HLA DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers (De Jager PL, 2008). Measles virus, with a molecular homology between MBP and measles virus hemagglutinin (Oldstone MBA, 1987) (See the results). Canine Distemper virus, a paramyxovirus like Measles virus (Cook S.D., 1995; Rohowsky-Kochan C., 1995), inducing in dogs a demyelinizing disease similar to MS. We found an homology between Canine Distemper virus and myelin oligodendrocyte glycoprotein (MOG). Human Herpes Virus type 6 (HHV-6) (Challoner, P. B, 1995; Friedman J.E., 1999) and Multiple Sclerosis Retrovirus MSRV (Perron H., 1999; Komurian-Pradel F., 1999). Herpes simplex virus type 1 may be also a very surprising candidate, as Herpes simplex virus type 1 ICP4 (NP_04462) sequence AAQARP is identical to an encephalitogenic peptide from modified (Alanine in position 4 instead of Lysine) MBP 1-AAQARP-6 (Pearson CI, 1999). for which we found an homology with bovine MBP NH2-terminus 1-AAQKRP-6. Bee Propolis which is more efficient than acyclovir in the treatment of herpes simplex virus type 1.
OBJECTIVE To link demyelinisation in MS and HAM/TSP to these viruses. METHOD: We compared amino acid sequences of MBP (human P02686), EBV, HTLV-1,-2, HHV-6 and MSRV.
RESULTS Abbreviations used A = Ala, Alanine; B = Asn or Asp, Asparagine or Aspartic acid; C = Cys, Cysteine; D = Asp, Aspartic acid; E = Glu, Glutamic acid; F = Phe, Phenylalanine; G = Gly, Glycine; H = His, Histidine; I = Iso, Isoleucine; K = Lys, Lysine; L = Leu, Leucine; M = Met, Methionine; N = Asn, Asparagine; P = Pro, Proline; Q = Gln, Glutamine; R = Arg, Arginine; S = Ser, Serine; T = Thr, Threonine; V = Val, Valine; W = Trp, Tryptophane; X = unknown; Y = Tyr, Tyrosine; Z = Gln or Glu, Glutamine or Glutamic acid 1°) We looked for MBP critical epitopes inducing in various experimental animals an experimental allergic encephalomyelitis (EAE): For example, the tryptophan is crucial, as its deletion abolished completely the encephalocitogenicity of MBP sequence RFSWGAEGQR; A computer BLAST research on MBP sequence RFSWGAEGQR revealed that Rhesus Cytomegalovirus (Hansen SG, 2003) contained the motif RFSWG identical to the motif we found manually in canarypox virus RFSW; interestingly, it has been published that a monkey cytomegalovirus may be found in multiple sclerosis. Another match was observed with influenza virus (B/Lee/40) ns1 protein sequence RFSW. Influenza virus C antibodies has been found in MS, and MS is aggravated by influenza infection; finally, we found manually RFSW motif also in Hepatitis B HBs surface antigen used in HBV vaccination, complicated by exacerbation and/or occurrence of MS in France (Revhab Association). MBP crucial residues for encephalitogenicity W QR MBP encephalitogenic sequence SLSRFSWGAEGQRPGF Rhesus Cytomegalovirus 128-RFSWGRD I RR-137 Measles virus nucleocapside 142-SRFGWF ENKE-151 Canarypox virus 218 RFSWVRYDDFEII Influenza virus type B ns1 rfswqraldypg Hepatitis B virus surface antigen HBs (vaccine) SVRFSWLSLLVPF 2°) VACCINIA VIRUS EPITOPE ILPDDIE Concerning vaccinia virus and MVA (modified vaccinia Ankara strain), another result was found by analyzing Canine distemper virus (CDV) hemagglutinin epitope 234 LVPDDIEREFDTREI 248 (Rohowsky-Kochan C, 1995); CDV is a measles-like neurotropic dog virus implicated by Cook SD (1995) in multiple sclerosis in Faroe Islands. Antibodies against this epitope 234-48 was found in sustained elevated titers in spinal fluid of MS patients, suggesting that MS is a zoonotic disease transmitted by dogs. We found by manual comparison an homology with marsupial myelin oligodendrocyte glycoprotein (MOG) 15 LVGDEIE 21; by computer BLAST research, we extended this core alignment to Murray Valley encephalitis, Venezuelian Equine encephalitis virus and vaccinia virus (serine protease inhibitor): Canine distemper virus hemagglutinin 234 LVPDDIE 240 Myelin Oligodendrocyte Glycoprotein (MOG) 15 LVGDEIE 21 Murray Valley encephalitis 168 AVIGPDDIE 176 Venezuelian Equine encephalitis virus ASLVPNEIE Vaccinia virus (serine protease inhibitor) 215 VIILPDDIE 221 Very interestingly, the Myelin Oligodendrocyte Glycoprotein (MOG) sequence 1-22 (containing 15- LVGDEIE-21) is encephalitogenic when injected in Biozzi AB/H mice (Amor S 1994), confirming that the homology is really of biological significance. 3°) We noticed also manually a striking homology of Canine Distemper Virus with interferon-beta VPEEIEQ: Canine distemper virus epitope 233 VPDDIER EFDTRE 247 Interferon-beta VPEEIEQAQQFQ KE Interferon-beta is efficient in some cases of multiple sclerosis, but the relationship between Canine Distemper Virus infected patients and the interferon response has not been explored until now. 4°) Concerning the sequence Alanine-Glycine-Alanine-Glycine-Glycine-Alanine AGAGGA (Cepok S, 2005), we found also an homology with Lyme’s disease Borrelia Burgdorferii, which is coherent with the presence of oligoclonal bands (OCB) in Lyme’s disease. Neurological symptoms of Lyme’s disease may present like and be confounded with multiple sclerosis. We found also this motif in HHV-6, a very good causal candidate for MS. 5°) A perfect molecular mimicry Proline-Arginine-Arginine-Proline-Proline-Proline between HTLV-2 Gag p17 and EBV EBNA-1 permitted to center the triproline alignment: MBP shark Lys Lys HHV-6 U24 Pro Arg Thr Pro Pro Pro Ser
CONCLUSION The demyelinisation observed in HAM/PST and MS is explained by a molecular mimicry/homology centered on a triproline motif PPP between myelin MBP and the 5 viruses found in these neurologic diseases: EBV, HHV-6 and MSRV (for MS), HTLV-1, -2 ( HAM/TSP) ; this is a molecular confirmation which reinforce and complete virus isolations. Interestingly, this MBP epitope is restricted by HLA DR2 (= DR15 = DR B1*1501), a crucial marker of susceptibility to MS; when injected to B10RIII (H-2r) mice, the 89-101 myelin basic protein peptide induced a chronic experimental allergic autoimmune encephalomyelitis (Jansson T, 1991) . It is rational to treat HAM/TSP and MS with antivirals specific of retrovirus and herpes viruses, including EBV. Interestingly, a published clinical trial with an anti-herpes drug in MS showed some results. Perhaps the results would be more convincing if a selection of MS patients restricted them to those infected by herpes virus family, avoiding non response from those infected by paramyxovirus and/or retrovirus: Thus, in the future, it would seem more efficent to define in a first step the different viral sub-groups and only then to treat them specifically with the corresponding anti-viral. Some kinds of anti-viral therapeutic vaccine like the dendritic cell vaccines (Srivasta P; and Nventa HSP-E7 against human papillomavirus) have proven their remarquable efficiency and constitute a promising avenue in the anti-viral armamentorium. Bee Propolis is also interesting against the herpes virus family. Addendum: The sequence mimicking Myelin Basic Protein PRTPPP, containing the triproline motif PKTPPP, is also present in T Antigen of Polyomavirus JC (Stoner GL, 1986a, 1986b, 1993), the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease encountered in AIDS.
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