C.57. TORONTO 2006: MYELITIS AIDS CANARYPOX AND VACCINIA VIRUS MVA VACCINE


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August 13-18, TORONTO, Canada.


AIDS vaccine-induced myelitis:

Canarypox virus 005 and spinal cord myelin basic protein

molecular homology at sequence GRDSRSGSPMARR with 2 citrullines.

TRAN Mong Ky Guy1*, CAPRANI A.2*

1 University Paris V, Corresp. : 31 Av. du Bois, 92290 Chatenay Malabry, France.
2 University Paris VII, Diderot, Paris, France.
* POSITIFS Association, Paris, France


INTRODUCTION

Canarypox virus based AIDS vaccine was stopped in USA (and also in France) after the occurrence of an acute myelitis case, suggesting that the species barrier between birds and humans (as for influenza and poliomyelitis virus) was broken by canarypox virus. In France, the vaccine did not contain canarypox virus but only lipopeptides, so the vaccination was retried after the verification of lipopeptides innocuity. Zagury D (1991) precedently had complications after vaccination with a vaccinia virus vector in HIV-1 patients, but this was forgotten: He reported cell immunotherapy with recombinant vaccinia that resulted in “wide necrosis” at the site of subcutaneous/intramuscular injections, resulting in death in 3 of 8 Aids patients; all 3 had CD4 counts less than 50 cells/mm3. Thus it seems that poxvirus family may represent a harmful family of viruses in AIDS patients.

In fact the acute myelitis observed with canarypox vaccine reminds the multiple sclerosis (MS) picture and discovery of anti-vaccinia virus antibodies in MS by various authors (Kempe CH, 1973; Thompson JA, 1975; Myamoto H, 1976).


post-vaccinal myelitis

post-vaccinal myelitis 2

post-vaccinal myelitis 3


OBJECTIVE

To understand the canarypox virus neurotoxicity in humans (canarypox when injected in birds did not induce myelitis).


METHODS

Jahnke U (1985) found a molecular homology between vaccinia virus 42K protein  (residues 253-261) and Myelin Basic Protein (MBP) FKLAGRDSR, explaining the vaccinia virus encephalomyelitis. By comparison of amino acid sequences, we screened for molecular mimicry between canarypox virus (40555938) (Tulman ER, 2004) and human spinal cord MBP (Roth HJ, 1987).


Abbreviations used

A = Ala, Alanine;    B = Asn or Asp, Asparagine or Aspartic acid;    C = Cys = Cysteine;    D = Asp or Aspartic acid;    E = Glu or Glutamic acid;    F = Phe or Phenylalanine;    G = Gly or Glycine;   H = His or Histidine;    I = Iso or Isoleucine;    K = Lys or Lysine;    L = Leu or Leucine;   M = Met or Methionine;   N = Asn or Asparagine;    P = Pro or Proline;    Q = Gln or Glutamine;    R = Arg or Arginine;    S = Ser or Serine;    T = Thr or Threonine;    V = Val or Valine;    W = Trp or Tryptophane;    X = unknown;   Y = Tyr or Tyrosine;   Z = Gln or Glu, Glutamine or Glutamic acid.


RESULT

                                                                                                               *                                     *
Human  spinal cord MBP           QGTLSKIFKLG GRDSRSGSPMARR
Shark spinal cord MBP                                                                                        P    ARR
Canarypox virus  005                RGKMTRVREPGASRDSRD–P    ARR
Measles virus (SSPE)                                      LK  PI IGRDSGR
Theiler’s virus (demyelinating strain) capside           GYRYDSRTG

Many encephalitogenic demyelinating viruses were clustered around GRDSR (arginine R of GRD and last R are citrullines (*) (*): Vaccinia virus (including AIDS vaccine Ankara strain), canarypox virus, measles virus [Subacute Sclerosing Pan Encephalitis (SSPE) strain], Theiler’s virus (demyelinating strain). Interestingly, the non encephalitogenic strain of Theiler’s virus did not align with MBP. The MBP peptide 153-FKLGGRDSRSGSPM-166 induced an auto-immune encephalomyelitis in monkeys (Karkhanis Y.D., 1975). A fulminant multiple sclerosis (Marburg type) occurred when arginines were deiminated in citrullines (Wood DD, 1996). This region is restricted by HLA-DR2 (Jacobson S., 1985).

The avian MBP sequence GRPSGSGSRSGSPVARR was different and did not contain the motif GRDSR, explaining why canarypox virus did not induce a myelitis in birds.

Three others results were found:
1) RFSW is common to MBP and canarypox virus; this epitope was first discovered by Oldstone MB (1987) who found a molecular homology with measles virus nucleocapside SRFGWFENKE;
2) vaccinia virus LSLTHFS is more homologous to myelin oligodendrocyte glycoprotein (MOG) FSRVVHL, which is encephalitogenic in Lewis mice (than to MBP GLSLSRFS and rabies GMSLGRF).
3) and vaccinia virus ILPDDIE was homologous to MOG encephalitogenic peptide LVGDEIE.

Canarypox Epitope RFSW

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.

MBP crucial residues for encephalitogenicity                         W              QR
MBP encephalitogenic sequence                             SLSRFSWGAEGQRPGF
Rhesus Cytomegalovirus                                                128-RFSWGRD I RR-137
Measles virus nucleocapside                                           SRFGWF   ENKE
Canarypox virus 218                                                             RFSWVRYDDFEII
Influenza virus type B ns1                                                  rfswqraldypg
Hepatitis B virus surface antigen HBs (vaccine)      SVRFSWLSLLVPF

 

VACCINIA VIRUS EPITOPE LSLTHF

The vaccinia virus [Histidine (H= His) containing] epitope LSLTHF was also found manually to be homologous to myelin oligodendrocyte glycoprotein (MOG) 44-FSRVVHLYRN-53 (Linington C, 1995), which is encephalitogenic in Lewis mice. An alignment was also found manually with MBP sequence NPVVHFFKN (Whitaker JN, 1990):

Vaccinia virus                             LS   LTHF
MOG                                        44-FSRVVHLYRN-53
MBP                                                 NPVVHFFKN

 

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 MOG sequence 1-22 IGPRHPIRALVGDEVE is encephalitogenic when injected in Biozzi AB/H mice (Amor S 1994), confirming that the homology is really of biological significance. We noticed also manually a striking homology of CDV 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 CDV infected patients and the interferon response has not been explored until now.


MOG 3D structure

 

CONCLUSION

There is a significant molecular homology on citrullines containing sequences RDSR between canarypox virus 005 and spinal cord MBP, shared by encephalomyelitogenic (vaccinia, measles, Theiler’s) viruses, suggesting an auto-immune myelitis after AIDS canarypox vaccine, possibly HLA-DR2 restricted. This neurotoxic epitope should be deleted in canarypox or modified vaccinia virus Ankara (MVA), although this does not eliminate completely other surprises, such as another encephalitogenic RFSW motif common to MBP, canarypox 218, measles virus nucleocapsid and HBV vaccine.

Concerning vaccinia virus and MVA (modified vaccinia Ankara strain), 2 epitopes were found homologous to MOG encephalitogenic regions. We confirm that canine distemper virus found in Faroe Islands multiple sclerosis (Cook SD) is homologous to a MOG encephalitogenic peptide, raising the old question of a zoonosis transmitted by dogs.

Canarypox virus and MVA may be deleterious vectors in vaccination of some HLA-restricted patients, and should be deleted, if used, of these encephalitogenic epitopes.



BIBLIOGRAPHY

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Cook SD, Rohowsky-Kochan C, Bansil S, Dowling PC.
Evidence for multiple sclerosis as an infectious disease.
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Hansen SG, Strelow LI, Franchi DC, Anders DG and Wong SW
Complete Sequence and Genomic Analysis of Rhesus Cytomegalovirus
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Jacobson S, Nepom GT, Richert JR, Biddison WE, McFarland HF.
Identification of a specific HLA DR2 Ia molecule as a restriction element for measles virus-specific HLA class II-restricted cytotoxic T cell clones.
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Jahnke U, Fischer EH, Alvord EC Jr.
Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis.
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Karkhanis YD, Carlo DJ, Brostoff SW, Eylar EH.
Allergic encephalomyelitis. Isolation of an encephalitogenic peptide active in the monkey.
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Kempe CH, Takabayashi K, Miyamoto H, McIntosh K, Tourtellotte WW, Adams JM.
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Oldstone MB.
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Thompson JA, Bray PF, Glasgow LA.
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Whitaker JN, Moscarello MA, Herman PK, Epand RM, Surewicz WK.
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Wood DD, Bilbao JM, O'Connors P, Moscarello MA.
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Zagury D.
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iconography from www.mribhatia.com/spinetf12/index.html



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