Vous êtes sur la page 1sur 13

Research Article

For reprint orders, please contact: reprints@futuremedicine.com

Measles virus hemagglutinin epitopes
are potential hotspots for crossreactions
with immunodeficiency-related proteins

Darja Kanduc*

Abstract Aims: Measles virus (MV) infection induces a protective immunity that
is accompanied by a transient pathologic suppression of the immune system. This
immunologic paradox remains unexplained in spite of the numerous hypotheses that have
been advanced (i.e., cytokine production, soluble immunosuppressive factor, cell cycle
block, signaling lymphocyte activation molecule receptor and MV infection of dendritic
cells, among others). Methods: Searching for molecular link(s) between MV infection and
host immunodeficiency, this study used the Immune Epitope DataBase to analyze the
peptide sharing between the antigenic MV hemagglutinin (H) protein and human proteins
associated with immunodeficiency. Results: It was found that the majority of MVH derived
epitopes share several exact pentapeptide sequences with numerous human proteins
involved in immune functions and immunodeficiency, such as B- and T-cell antigens,
and complement components. Conclusion: The data suggest that crossreactivity might
contribute to our understanding of the link between MV immunogenicity and MV-induced
immunosuppression, and highlight peptides unique to MV as a basis for developing effective
and safe anti-MV vaccines.

Measles virus (MV) infection and, to a lesser extent, anti-MV vaccination induce a protective Keywords 
immune response associated with a transient immunosuppression that is the major cause of the • immunodeficiency-
current high morbidity and mortality rate associated with MV disease [1–3] . associated proteins
The relationship between measles infection/vaccination and the decay of the immune function • MVH-derived epitopes
has been the object of intensive investigations [1–5] . The timing of the immunosuppression appears • MV immunogenicity
to be related to the antibody production in an infected individual [2] , as also indicated by the fact • MV-induced
that antibody-dependent enhancement of MV infection in mouse and human macrophages has immunosuppression
been described [6] . Moreover, induction of maturation of dendritic cell (DC) precursors with both • peptide crossreactivity
MV vaccine and wild-type strains is accompanied by a negative DC signaling to inhibit lymphocyte • peptide sharing
proliferation that contributes to MV-induced lymphopenia [7] .
Many molecular events appear to be involved, for example, downregulation of IL-12 production [8] ;
interference with induction of alpha/beta IFN production [9] ; abnormal differentiation of CD40
ligand-activated human DCs [10] . Receptor usage may also contribute to MV-induced lymphopenia
and immunosuppression [11] . Wild-type MV propagates by using signaling lymphocyte activation
molecule (also called CD150) in lymphoid organs and nectin-4 in epithelial tissues, while MV vaccine
uses a complement-regulatory molecule, CD46, as a receptor [11–15] . In addition, it is known that the
complex of MV fusion (F) and H glycoproteins induces immunosuppression in vitro [16] . The MV F-H
complex silences T cells by activating cellular sphingomyelinases in a contact-dependent manner, thus
interfering with signaling pathways essential for T-cell activation [17,18] . Finally, it has to be considered

*Department of Biosciences, Biotechnologies & Biopharmaceutics, University of Bari, Bari, Italy; dkanduc@gmail.com part of

10.2217/FMB.14.137 © 2015 Future Medicine Ltd Future Microbiol. (2015) 10(4), 503–515 ISSN 1746-0913 503

In the present study. The analyzed MVH-derived epitopes were tifactorial phenomenon with an immune response retrieved from the Immune Epitope Database that is diversified and dislocated in time. The authors concluded that MV that MVH-derived epitopes have the potential infection wipes out immunological memory. Prot entry: Q9IC33_MEASZ. utilizing tide overlap represent a link between immune ‘immune system. the present study human protein library was randomly derived poses the question: may MV versus human pep. QRDRI and RDRIN. Indeed.com/doi/suppl/10. Human proteins are reported as viral epitopic sequences targeted by the immune UniProtKB/Swiss-Prot entry names throughout system might contain the key to understand the the paper. an immune response against derived from MVH protein (UniProtKB/Swiss- the pathogen may result in humoral and/or cel. immune functions and immunodeficiency. massive pathogen versus human pentapeptide PQRDR. bacterial/viral agents share epitopic sequences This study focused on linear epitopes that were with host proteins. second. and that had been experimentally tested sharing between pathogens and the human pro.futuremedicine. positive or underlie the pathological nexus between the had produced mixed negative/positive results human host and infectious agents. Since 2000. protein. Next. it appears that Methods measles-associated immunosuppression is a mul.Research Article Kanduc that anti-MV antibodies (Abs) are present life. With respect to this point. as positive in the human host. reports from this lab have acteristics.137). validated as negative. involved in immune system functions. The structure.14.22] and. NCBI Taxonomic tivity scenario is of extreme relevance in light of identifier: 70149). thus suggesting to months. from different strains and with different char- lyzed. sclerose panencephalitis virus. at www. Overall. the notion that selection criteria.40] . To identify peptide motifs unique to MVH Following this rationale. when in immunoassays. 73 MVH-derived epitopes a 5-amino acid grouping plays a basic role in were found and analyzed.2217/ tion [1–7] . Specifically. validated in different hosts.’ ‘immunodeficiency’ and ‘Homo response and immunosuppression in MV sapiens’ as keywords. tious agents that would normally be controlled by the immune system [19] . unless when discussed in detail. the one residue each other (i. that were not longer than 15 two factors: first. Data are that following initial MV-induced lymphopenia.e. At the time of the analysis. Based on these teome (>90%) [21. de Swart’s lab [19] for pentapeptide sharing with human proteins performed in vivo studies in macaques and found associated with immunodeficiency. reported showing that MVH-derived epitopes lymphocyte counts rapidly return to normal after are mostly formed by peptide fragments also pre- clearance of the virus. whereas immune suppression is only tran. of different lengths (up to 32 amino data suggested that peptide crossreactivity may acids [aa]). MV infection-induced immunosuppression. the database contained described a massive peptide sharing between MVH epitopes linear or conformational in the microbial and human proteins [20–24] . Indeed. from UniProtKB Database [39. MSPQR. The keyword-guided search infection? Since protective anti-MV immune produced a list of 1793 proteins that are syntheti- responses and pathologic immunosuppression cally described in Supplementary Table 1 (see online are temporally related following MV infec. among others). (2015) 10(4) future science group . Actually the crossreac. the potential role of viral IEDB contained 174 MVH-derived epitopes versus human immune crossreactivity was ana.. leav. 617aa) [39] from lular crossreactions able to hit and damage the strain Edmonston–Zagreb vaccine (or subacute host components [25–29] . to induce crossreactions with human proteins ing individuals susceptible to opportunistic infec. thus posing the question of sent in human proteins associated with immuno- why immune suppression then lasts several weeks deficiency and immune system. each MVH pentapeptide was used as a dated epitopes from MV hemagglutinin (MVH) probe to search the entire human proteome for 504 Future Microbiol. (IEDB  [37])  [38] . – a well-known antigenic and immunogenic long. MV protein [33–36] – have been here explored sient. overlap and the fact that a pentapeptide is suf. Each epitope was dis- antigen-antibody recognition and in humoral/ sected into overlapping pentapeptides offset by cellular immune reactivity [30–32] . experimentally vali. each viral pentamer was analyzed for ficient to evoke an immune response mean that occurrence(s) within a library containing pri- immune reactions following infections may be mary sequences of human proteins involved in a considerable source of crossreactions. The In this scientific framework. SPQRD. the dimension of the peptide aa. it seemed logical to hypothesize that fmb.

agammaglobulinemia with binding potential [46–51] .com 505 . such Analysis of the peptide sharing between as CD14. numerically. The overall picture of the pentapeptide overlap Table 1 also shows that. an anti- MVH protein from Edmonston wild strain. canonically represented by peptides 9–15-aa long. In addition. with B. Sequence align. teins CO2. Obviously. CD24. As to immunodeficiency was conducted on the viral regards this latter potential target of crossreac- H protein since. and consequent persistent infec- references therein). pentapeptides as scanning probes based on the Clinically. 39483. consequent severe infections in the first years of ple of the crucial role exerted by small peptide life (CD79B) [56] . immediate datum that emerges from the FEVGV with three B-cell epitopes (IEDB IDs analysis of Table 1 is that only six out of the selected 9929.45] . MV-derived epitopes and human proteins related CD3D. MVH immune response crossreacting with CO2. Indeed. and CO6.2. recurrent bacterial and opportunistic infections. immunologic defect leading to modules in MV immunobiology is the MVH recurrent bacterial infections (CD8A) [57] . alterations in these CD molecules validated concept that a grouping of five aa resi.and T-cell MVH-derived epitopes. Table 1 ClustalW2 program [43] . For example: ficiency-associated proteins is reported in Table 1. CD1C. the between MVH-derived epitopes and immunode. CD36. constitutes an epitope recognized by the anti. crossreactome between MVH & immunodeficiency-associated proteins ●● SHIP2 shares pentapeptides AAEEL and A first. AF266288. impairment of both humoral and cell-mediated tion and immunoreactivity ([31. CD5L. 219 human pro. have been involved in: immunodeficiency with dues represents a quantum in immunorecogni. thus predisposing individ- sequence similarity analyses. and of intractable diarrhea due to Cryptosporidium infec- flanking residues. it is of note to recall that abnormal ture [33–36. CD40L. MVH protein antigens described above also offers a chance to entirely lost its reactivity with MAb E128 when observe that CD molecules are spatially located carrying aa substitutions at positions 473 to 477 on the surface of B or T cells. in many instances. MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  Research Article instances of the same pentapeptide using the proteins. The analysis used DCs is induced by MV [10] . 73483 and 56283) and one T-cell epitope 73 MVH epitopes are exempt from pentapeptide (IEDB ID 59787) for a total of four matches. CD34.44. CD38. CD79B. CD8A. matches with the immunodeficiency-associated Alterations of SHIP2 are involved in future science group www. tions. also T-cell epitopes. which pro. CD40L. Altered AP3B1 is involved in an increased susceptibility to Description of the potential peptide infections [58] . tions by opportunistic organisms (CD3D) [54] . peptide overlap is multiple. SLLDL It can be seen that. IEDB IDs 42603. a receptor for MV words. might de facto represent privileged targets vaccine strains [52] . as indicated by an ample litera. MVH pentapeptides with no in the human defense system as complement pro- matches to the human proteome were recorded. the MVH is a main target of the differentiation of CD40 ligand-activated human humoral immune responses.32] and pertinent immunity. A paradigmatic exam. The remaining 67 viral epitopes share Protein International Resource (PIR) peptide peptides with human proteins crucially involved match program [41] . thus being highly and the same pentapeptide region is involved in accessible to crossreactive attacks. the peptide sharing between MVH and the CD MVH MAb E128 [35] . shows that the peptide sharing involves cluster differentiation (CD) antigens associated with Results & discussion B. CO3. in immune crossreactions. NCBI Taxonomic identifier CO3 and CO6 might lead to deficiencies of such 11234 [42] was used as a control in comparative complement proteins. Moreover. which determine the peptide tion (CD40L) [55] . and TVELK (with SLLDL and TVELK teins involved in the modulation and regulation repeated twice) with five MVH-derived B-cell of immune functions share peptide sequences epitopes (see Table 1. 39732 and 7279).futuremedicine. consist of a core pentapeptide motif. 23048.and T-cell development and maturation. ●● AP3B1 shares pentapeptides DSESG. in other the interaction with CD46. including Pneumocystis carinii pneumonia and vides the majority of the specific contacts. uals to recurrent respiratory infections and infec- ment of MVH protein from Edmonston vaccine tions caused by encapsulated organisms including strain and the wild one was carried out by using Streptococcus pneumonia  [53] . pentapeptide IPRFK (aa position 473–477) that In the scientific context of the present study.

AAEEL) SHIP2 (AAEEL) PDC6I (AAEEL) DAB2P (AAEEL) M3K14 (AEELM) NCOA1 (EELMN) 153 73483 YCADVAAEELMNALV B cell RAE1L (YCADV. HLA-class II DOCK2 (FYKDN) 29 24256 hlmidrpyv T cell. T cell.. # Further data and related references from [37]. ‡ Epitope IEDB ID from [37]. §§ Proteins sharing two overlapped pentapeptides (e. § Amino acid sequence given in one-letter code. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency.§§. HLA-A2.506 Table 1. HLA-A2 PDIA3 (FISDK) CATE (SDKIK) PPARG (DKIKF) Future Microbiol.g. (2015) 10(4) 123 30774 kflnPDREYdFRDLT B cell CFAH (PDREY) SC24B (FRDLT) 133 17572 FRDLTWCINPPERIk B cell SC24B (FRDLT) CD38 (DLTWC) NUP88 (CINPP) ABL1 (PPERI) ADCY1 (PPERI) 143 47398 pERIKLdyDQYCADV B cell M3K1 (ERIKL) COG1 (DQYCA) NOTC2 (QYCAD) RAE1L (YCADV) 151 9929 DQYCADVAAEELMNa B cell COG1 (DQYCA) NOTC2 (QYCAD) RAE1L (YCADV. HLA-A2 IRAK3 (VMFLSL) PRL (FLSLI) Research Article Kanduc 73 59483 SLSTNLDVtnsiehq B cell IFNA1 (SLSTNL) IFNA2 (SLSTNL) M3K3 (SLSTN) TRI11 (LSTNL) DUS6 (STNLDV) DUS7 (STNLDV) 83 58485 siEHQVKDVLtplfk B cell JAK1 (EHQVK) IFIT1 (HQVKD) KI20A (VKDVL) KIF5A (VKDVL) KINH (VKDVL) SCF (VKDVL) 93 65635 tplfKIIGDEVGLRT B cell PSME4 (KIIGD) ITB1 (IGDEVG) ASB16 (VGLRT) 101 8195 deVGLRTPQRFTdlv B cell ASB16 (VGLRT) MRC2 (GLRTP) IF16 (LRTPQ) TRI25 (PQRFT) 103 68723 VGLRTPQRFTdlvkf B cell ASB16 (VGLRT) MRC2 (GLRTP) IF16 (LRTPQ) TRI25 (PQRFT) 113 9319 dLVKFISDKIKFlnp B cell PDC6I (LVKFI) HERC2 (KFISD) PDIA3 (KFISDK) CATE (SDKIK) PPARG (DKIKF) 117 16290 FISDKIKFl T cell. HLA-class II DRB3 (PYVLL) NCKP1 (PYVLL) TRIB3 (PYVLL) PANX1 (YVLLA) FGFR4 (VLLAV) TARB1 (VLLAV) VGFR2 (VLLAV) CD34 (LLAVL) HUWE1 (LLAVL) ITAV (LLAVL) SKIV2 (LLAVL) APOA1 (LAVLF) CUL5 (LAVLF) CYLD (AVLFV) 41 69496 vlfVMFLSLIGLLAI T cell IRAK3 (VMFLSL) PRL (FLSLI) CTNB1 (GLLAI) LAX1 (GLLAI) TREX1 (GLLAI) 41 69495 vlfVMFLSLI T cell. Position† IEDB ID‡ Epitope sequence§.‡‡.¶ Epitope immune context# Human immunodeficiency proteins sharing peptides with MVH††. T cell.¶¶  1 42622 mspqrdrinaFYKDN T cell. MVH: Measles virus hemagglutinin. – HLA-A*02:01 31 41693 midrPYVLLAVLFVm B cell. †† Proteins given by UniProtKB/Swiss-Prot entry names. ‡‡ In parentheses. ¶¶ future science group Proteins sharing two pentapeptides are given underlined. shared pentapeptide(s) given in italic. AAEEL) SHIP2 (AAEEL) PDC6I (AAEEL) DAB2P (AAEEL) M3K14 (AEELM) NCOA1 (EELMN) VPRBP (MNALV) 163 42187 MNALVNSTLLEtrtt B cell VPRBP (MNALVN) TANK (LVNST) BAIP2 (NSTLL) TACT (NSTLL) M3K1 (STLLE) MYO9B (STLLE) 173 14536 etRTTNQFLAVSKGN B cell TRAD1 (RTTNQ) UCHL3 (TNQFL) COG5 (LAVSK) AP2A1 (AVSKG) AP2A2 (AVSKG) KI2S5 (VSKGN) TEN1 (VSKGN) 183 71009 VSKGNCSGPTTIRgq B cell KI2S5 (VSKGN) TEN1 (VSKGN) EGF (KGNCS) IL1RA (SGPTT) RFX5 (SGPTT) SIPA1 (PTTIR) 193 64444 tiRGQFSNMSLSLLD B cell CLH1 (RGQFS) TLR10 (SNMSL) SC23A (MSLSLL) BIRC1 (SLSLL) CD24 (SLSLL) CD40L (SLSLL) IFIT1 (SLSLL) KLOT (SLSLL) TPSN (SLSLL) CREB3 (LSLLD) NFKB1 (LSLLD) 201 42603 MSLSLLDLYLGRGyn B cell SC23A (MSLSLL) BIRC1 (SLSLL) CD24 (SLSLL) CD40L (SLSLL) IFIT1 (SLSLL) KLOT (SLSLL) TPSN (SLSLL) CREB3 (LSLLD) NFKB1 (LSLLD) AP3B1 (SLLDL) MALT1 (SLLDL) TTC37 (LLDLY) TFE3 (YLGRG) 203 39483 LSLLDLYLGRGYNVS B cell CREB3 (LSLLD) NFKB1 (LSLLD) AP3B1 (SLLDL) MALT1 (SLLDL) TTC37 (LLDLY) TFE3 (YLGRG) ARPC2 (GYNVS) † Amino acid position along the measles virus hemagglutinin sequence. IEDB: Immune Epitope Database . a hexapeptide) are given in bold. . HLA-A*02:01 – 30 38042 lmidrpyvl MHC binding. ¶ Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals.

. Table 1. ‡ Epitope IEDB ID from [37]. DCTN6 (VFEVG) M3K11 (VFEVG) SHIP2 (FEVGV) HLA-A*02:01 253 56283 rVFEVGVIRNPGLGA B cell DCTN6 (VFEVG) M3K11 (VFEVG) SHIP2 (FEVGV) IFNA8 (EVGVI) IKKA (EVGVI) MYO1E (GVIRN) CD14 (NPGLG) ATRN (PGLGA) CBP (PGLGA) IKBB (PGLGA) PRKDC (PGLGA) 263 47694 PGLGAPVfhmtnyle B cell ATRN (PGLGA) CBP (PGLGA) IKBB (PGLGA) PRKDC (PGLGA) SKIV2 (LGAPV) 283 9281 dlsncmVALGELKLa B cell CDC23 (VALGE) RO52 (VALGEL) CUL1 (LGELK) EGF (LGELK) KPCD (LGELK) PRKDC (LGELK) SMAL1 (LGELKL) 293 13126 elKLAALCHGEDSIT B cell NU133 (KLAAL) PI3R4 (KLAAL) EGFR (LAALC) ERBB2 (LAALC) RBP2 (LAALC) TXLNG (KLAALC) UBE2O (HGEDS) KIF4A (EDSIT) 303 11441 EDSITIPYQGSGKGv B cell KIF4A (EDSIT) GLGB (DSITI) RFX1 (PYQGS) ITPR3 (GSGKG) STAT2 (GSGKG) 311 50957 qGSGKGVSFQLVKLg B cell ITPR3 (GSGKG) STAT2 (GSGKG) EGFR (GKGVS) IL17F (VSFQL) DDB1 (QLVKL) UBR4 (QLVKL) 313 58103 sGKGVSFQLVKLgvw B cell EGFR (GKGVS) IL17F (VSFQL) DDB1 (QLVKL) UBR4 (QLVKL) 323 31894 klgvwKSPTDmqswv B cell DBNL (KSPTD) 333 42413 mQSWVPLSTddpvid B cell FOXO3 (QSWVP) PI3R4 (VPLST) 343 9804 dPVIDRLYLSShrgv B cell GLGB (PVIDR) ERAP2 (PVIDR) IKKE (LYLSS) 353 58403 shRGVIADNQAKwav B cell BLK (RGVIA) TARB1 (ADNQA) TRIPC (DNQAK) 363 2322 aKWAVPTTRTDDKLr B cell EPG5 (KWAVP) FA12 (PTTRT) ITB3 (TTRTD) PK3CA (TDDKL) www.¶ Epitope immune context# Human immunodeficiency proteins sharing peptides with MVH††.¶¶  211 22063 grGYNVSSIvtmtsq B cell ARPC2 (GYNVS) EXO1 (NVSSI) 213 23422 GYNVSSIvtmtsqgm B cell ARPC2 (GYNVS) EXO1 (NVSSI) 223 66385 tsQGMYGGTYLVEKP B cell S5CGQ1 (QGMYG) LV209 (YGGTY) SNF8 (GGTYL) SPSB2 (GGTYL) ITK (YLVEK) ASB10 (LVEKP) IGS22 future science group (LVEKP) 233 40319 LVEKPNLSSKRSELS B cell ASB10 (LVEKP) IGS22 (LVEKP) CO3 (EKPNLS) GNPTA (NLSSK) LAP2A (LSSKR) CO6 (SSKRSE) NFAC1 (SSKRS) VAV (KRSELS) MYO1C (RSELS) NHEJ1 (RSELS) TRAF3 (RSELS) 236 32807 KPNLSSKRSELSQLS B cell CO3 (KPNLS) GNPTA (NLSSK) LAP2A (LSSKR) CO6 (SSKRSE) NFAC1 (SSKRS) VAV (KRSELS) MYO1C (RSELS) NHEJ1 (RSELS) TRAF3 (RSELS) SATB1 (SELSQ) TLR3 (ELSQLS) FBX3 (LSQLS) SOS1 (LSQLS) TXK (LSQLS) TYK2 (LSQLS) 243 55826 RSELSQLSmyrvfev B cell MYO1C (RSELS) NHEJ1 (RSELS) TRAF3 (RSELS) VAV (RSELS) SATB1 (SELSQ) TLR3 (ELSQLS) FBX3 (LSQLS) SOS1 (LSQLS) TXK (LSQLS) TYK2 (LSQLS) 248 51546 qlsmyrvfev B cell – 250 59787 smyrVFEVGV MHC binding. †† Proteins given by UniProtKB/Swiss-Prot entry names. ¶¶ Proteins sharing two pentapeptides are given underlined. shared pentapeptide(s) given in italic. ‡‡ In parentheses.com 373 7812 dDKLRMEtCFQQAck B cell SPN90 (DKLRME) RPGF1 (CFQQA) 383 52000 qqackgKIQALCENp B cell ASB6 (KIQAL) CATF (KIQAL) PO210 (KIQAL) TLR3 (KIQAL) DB127 (ALCEN) MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  393 35050 lCENPEWAPLKDnri B cell CD5L (CENPE) SEM4A (NPEWA) ZEP2 (PEWAP) DNM3B (APLKD) 403 30220 kdnripSYGVLSVDL B cell CD36 (SYGVL) KS6A1 (SYGVL) UBR4 (GVLSV) BIRC1 (LSVDL) ITPR2 (LSVDL) † Amino acid position along the measles virus hemagglutinin sequence.§§. MVH: Measles virus hemagglutinin. HLA-A2. a hexapeptide) are given in bold.). Research Article 507 . §§ Proteins sharing two overlapped pentapeptides (e. § Amino acid sequence given in one-letter code. # Further data and related references from [37]. T cell. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency (cont.‡‡.futuremedicine. IEDB: Immune Epitope Database .g. Position† IEDB ID‡ Epitope sequence§. ¶ Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals.

‡ Epitope IEDB ID from [37]. (2015) 10(4) 503 14641 evdGDVKLSSNLVIL B cell M4K2 (GDVKL) MASP2 (VKLSS) PK3CD (VKLSS) NEMO (VKLSS) IF4E (LSSNL) KS6A2 (LSSNL) TLR8 (LSSNL) CO2 (SSNLV) BAIP2 (SNLVI) ITPR1 (SNLVI) DDX58 (NLVIL) 513 44915 NLVILPGQDLQyvla B cell DDX58 (NLVIL) UBA3 (VILPG) ADCY8 (ILPGQ) CO3 (PGQDL) EGF (GQDLQ) 516 27245 ILPGQDLQyv MHC binding. .. T cell. §§ Proteins sharing two overlapped pentapeptides (e.¶¶  411 23048 GVLSVDLSLTVELKi B cell UBR4 (GVLSV) BIRC1 (LSVDL) ITPR2 (LSVDL) PPARG (SVDLS) TSC2 (SVDLS) CDN1A (VDLSL) STAT2 (SLTVE) AP3B1 (TVELK) CD8A (TVELK) 413 39732 LSVDLSLTVELKIKI B cell BIRC1 (LSVDL) ITPR2 (LSVDL) PPARG (SVDLS) TSC2 (SVDLS) CDN1A (VDLSL) STAT2 (SLTVE) AP3B1 (TVELK) CD8A (TVELK) KPCE (LKIKI) 421 68272 veLKIKIASGFgpli B cell KPCE (LKIKI) ATM (KIASGF) 423 36890 LKIKIASGFgplith B cell KPCE (LKIKI) ATM (KIASGF) 433 48370 pLITHGSGMDLYKSn B cell GLGB (LITHG) AL14E (SGMDL) OAS2 (DLYKS) SC24D (DLYKS) 443 40826 lyksnhnnVYWLTIp B cell TEN1 (VYWLTI) 453 72808 wLTIPPmKNLALGVi B cell SKIV2 (LTIPP. HLA-A*02:01 CFAI (SPYLF) DSRAD (YLFNV) 483 17243 fnVPIKEAGEDchap B cell SPT5H (VPIKE) PTPRC (PIKEA) ITAM (KEAGE) TPR (KEAGE) IRS1 (EAGED) ITPR1 (EAGED) RFXAP (EAGED) 493 7704 dchaPTYLPAEVdgd B cell PI3R4 (PTYLP) NFAC1 (TYLPA) NFAC1 (TYLPA) IFIH1 (LPAEV) Future Microbiol. T cell. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency (cont.).‡‡. ¶ Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals. Position† IEDB ID‡ Epitope sequence§. shared pentapeptide(s) given in italic. ¶¶ future science group Proteins sharing two pentapeptides are given underlined. ALGVI) ZEP2 (LTIPP) NCKP1 (KNLAL) RPC2 (KNLAL) UBA3 (KNLAL) RAD50 (NLALG) Research Article Kanduc 2AAA (LALGV) 2AAB (LALGV) ALG8 (LALGV) CD3D (LALGV) 463 2598 ALGVINTLEwiprfk B cell SKIV2 (ALGVI) CBP (VINTL) KIF11 (INTLE) 473 28041 iPRFKVSPYLFNVpi B cell SPB3 (PRFKV) ABI2 (RFKVS) CFAI (SPYLF) DSRAD (YLFNV) 477 34206 kvSPYLFNV MHC binding. ‡‡ In parentheses. DSESG) RNF6 (ADSES) AP3B1 (DSESG) CD1C (DSESG) UBR4 (SESGG) XPO1 (GGHIT) 603 23134 GVSCTVTREDGTNRr B cell CD79B (GVSCT) NU153 (SCTVT) IL1R2 (VTRED) KEAP1 (DGTNR)   † Amino acid position along the measles virus hemagglutinin sequence. HLA-A2. ADCY8 (ILPGQ) CO3 (PGQDL) EGF (GQDLQ) HLA-A*02:01 523 53046 qyvlatyDTSRVeha B cell MASP1 (DTSRV) 531 66410 tsrvehaVVYYVYSp B cell KPCD1 (VVYYV) PLXA1 (YYVYS) 553 75287 ypfRLPIKgVPIELq B cell FAK2 (RLPIK) C531 (RLPIK) CUL7 (VPIEL) 561 23096 gVPIELQVECftwdq B cell CUL7 (VPIEL) PGFRB (ELQVE) PSD12 (ELQVE) COG4 (LQVEC) KIF5A (LQVEC) 563 47890 piELQVECftwdqkl B cell PGFRB (ELQVE) PSD12 (ELQVE) COG4 (LQVEC) KIF5A (LQVEC) 573 72324 wdqklwcrhfcvlad B cell – 576 32241 klwcrhfcv MHC binding. § Amino acid sequence given in one-letter code.§§. # Further data and related references from [37]. – HLA-A*02:01 576 32242 klwcrhfcvl T cell. †† Proteins given by UniProtKB/Swiss-Prot entry names. MVH: Measles virus hemagglutinin. IEDB: Immune Epitope Database .508 Table 1. a hexapeptide) are given in bold. HLA-A2 – 583 7279 cVLADSESGGHIThs B cell I10R2 (VLADS. HLA-A2.g.¶ Epitope immune context# Human immunodeficiency proteins sharing peptides with MVH††.

reduce the viral load. on one hand. In primis. Table 2 suggests that crossreactivity may well 47694. ●● SKIV2 has five pentapeptide matches (LGAPV.3% from the may reboot lymphocyte proliferation [66. Being highly conserved tus. to prevent infection or disease but facilitate sub- The high level of conservation of wild-type sequent clearance of viral RNA [5. IEDB ID 41693. MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  Research Article diabetes [59] and might represent a link between immunodeficiency consequences as a common diabetes and anti-MV immune responses [60] . the anti-MV immune responses that that only a few aa substitutions (namely 5 aa follow MV infection/vaccination. Hence. at the same time. vaccine sequence and searched for the peptide Moreover.63] . may one. It seems pertinent to mention that vac- in the MVH from the Edmonston wild strain cine-induced MV-specific T cells do not appear (Table 2. so that hitting IPRFK might affect Next. although bur- changes. the MVH measles-specific antibody titer after vaccination Edmonston wild strain [42] was aligned with the is lower than after natural infection [64] . In Edmonston wild strain [62. 72808. is also a T-cell epitope). persistence  [66–68] so that a decreased viral load cine viruses differed at most by 0. an immune response directed against a careful analysis of MVH-derived epitopes the B-cell epitope KPNLSSKRSELSQLS (see shows that two B-cell epitopes (IEDB ID: 2598. the conservativeness of MV wild- LLAVL. as recalled above.69] . Consequential to such a sequence conserva. 41693. tions and may correlate with viral clearance or In agreement with reports showing that vac. IPRFK that. given the common To add complexity to the potential crossreac.and T-cell crossreactive responses. immediately subsequent massive postvaccination immune responses have similar expansion of MV-specific lymphocytes. LTIPP. For Table 1 suggests a rational explanation. as shown in Table 2 . one of which. a receptor for MV vaccine epitopic peptide sharing strains  [52] . residues given bold) differ. example. aa sequences given underlined). on the other hand. the majority of MVH epitopes share pep. peptide sharing illustrated in Table 1 was exclu. In secundis. also the epitope sharing with immuno. see Table 2. Indeed. delete B. constitutes an epitope recognized by the anti-MVH mAb MVH from Edmonston vaccine & wild E128  [35] . In this regard. Actually. In fact. immunotolerance mechanisms and progressively Table 2 might reasonably explain why immuno. and tion and vaccination. dened by a crossreactive potential that concurs in entiate the vaccine strain MVH from the wild establishing lymphopenia. one would expect tome. Table 1. Table 2 illustrates other words. crossreactivity appears to be at the the epitopic peptide sharing described in Table 1. it does not explain the different extent of the immunosuppression. To this aim. This pentapeptide is involved in the strains: comparative analysis of the interaction with CD46. the possibility of multiple crossreactivity.com 509 . Rebooting and vaccine MV Edmonston sequences offers lymphocyte proliferation and restoring the the chance to discuss two main points related to immune activity might also ripristinate the host MV-associated immunosuppression. denominator. immunodeficiency [61] . antigen load and lymphopenia have platform shared with immunodeficiency-related been found to be inversely related in viral infec- antigens described above in Table 1. the basis for progressively restoring the immune deficiency-related antigens is highly conserved activity. plus ALGVI repeated twice) type and vaccine sequences poses the problem of disseminated through four MVH B-cell explaining the much weaker immunosuppression epitopes (IEDB IDs 2598. that MV wild type and vaccine had pathologic tides with numerous proteins. clear/decrease the viral antigen load. IEDB ID 32807) might potentially ALGVINTLEWIPRFK. and IEDB ID: 28041.futuremedicine. In fact. and future science group www. and that follows vaccination. crossreact with 15 crucial proteins related to IPRFKVSPYLFNVPI) host the pentapeptide the immune function. then. epitopic platform (Tables 1 & 2). ciated immunodeficiency phenomenon. basis of the contradictory sequela of MV-induced it appears to be logical that postinfectious and lymphopenia.67] . thus posing tiveness. even- suppression associates with both MV infection tually eliminating the immunosuppression sta- and MV vaccination. Alterations in SKIV2 appear represent a contributing factor in establishing to be involved in a hepatoenteric syndrome immunosuppression following both MV infec- characterized by severe diarrhea in infancy. it was investigated whether the epitopic MV vaccine propagation. and moderate the immune response and the asso- sively associated with the measles vaccine strain. thus suggesting consequences of similar extent.

it has to be noted that notolerance mechanisms in the course of weeks the present MVH analysis is not exhaustive of the to months. However. Strain† Location of epitopic sequences‡. decrease of the viral antigen may favor the immunodeficienty phenomenon load. Moreover. further details are provided in ‘Methods’ section. experimental research in order to understand and phocyte activation molecule and CD209 cellular define a possible contribution of crossreactivity to receptor gene single nucleotide polymorphisms MV-induced immunosuppression.1 sequence alignment program [43]. with variations in MV vaccine-induced immune responses  [70] . Finally. the most immediate effects of viral load variability that may characterize of crossreactivity would be lymphopenia and. ¶ Amino acid substitutions are given in bold. malnourishment.Research Article Kanduc immunosuppression lasting several weeks to aspects of the MV immunology. other MV proteins may also play an important It is mandatory to underline the speculative role. the scientific-clinical This study might also offer approaches toward complexity of the MV infection.§. § Sequences relative to the epitopic peptide sharing found with vaccine strain (see Table 1) are underlined.¶ Amino acid position A  MSPQRDRINAFYKDNPHPKGSRIVINREHLMIDRPYVLLAVLFVMFLSLIGLLAIAGIRL 60 B MSPQRDRINAFYKDNPHPKGSRIVINREHLMIDRPYVLLAVLFVMSLSLIGLLAIAGIRL 60 A HRAAIYTAEIHKSLSTNLDVTNSIEHQVKDVLTPLFKIIGDEVGLRTPQRFTDLVKFISD 120 B HRAAIYTAEIHKSLSTNLDVTNSIEHQVKDVLTPLFKIIGDEVGLRTPQRFTDLVKFISD 120 A KIKFLNPDREYDFRDLTWCINPPERIKLDYDQYCADVAAEELMNALVNSTLLETRTTNQF 180 B KIKFLNPDREYDFRDLTWCINPPERIKLDYDQYCADVAAEELMNALVNSTLLETRTTNQF 180 A LAVSKGNCSGPTTIRGQFSNMSLSLLDLYLGRGYNVSSIVTMTSQGMYGGTYLVEKPNLS 240 B LAVSKGNCSGPTTIRGQFSNMSLSLLDLYLSRGYNVSSIVTMTSQGMYGGTYLVEKPNLS 240 A SKRSELSQLSMYRVFEVGVIRNPGLGAPVFHMTNYLEQPASNDLSNCMVALGELKLAALC 300 B SKRSELSQLSMYRVFEVGVIRNPGLGAPVFHMTNYLEQPVSNDLSNCMVALGELKLAALC 300 A HGEDSITIPYQGSGKGVSFQLVKLGVWKSPTDMQSWVPLSTDDPVIDRLYLSSHRGVIAD 360 B HGEDSITIPYQGSGKGVSFQLVKLGVWKSPTDMQSWVPLSTDDPVIDRLYLSSHRGVIAD 360 A NQAKWAVPTTRTDDKLRMETCFQQACKGKIQALCENPEWAPLKDNRIPSYGVLSVDLSLT 420 B NQAKWAVPTTRTDDKLRMETCFQQACKGKIQALCENPEWAPLKDNRIPSYGVLSVDLSLT 420 A VELKIKIASGFGPLITHGSGMDLYKSNHNNVYWLTIPPMKNLALGVINTLEWIPRFKVSP 480 B VELKIKIASGFGPLITHGSGMDLYKSNHNNVYWLTIPPMKNLALGVINTLEWIPRFKVSP 480 A  YLFNVPIKEAGEDCHAPTYLPAEVDGDVKLSSNLVILPGQDLQYVLATYDTSRVEHAVVY   540 B NLFTVPIKEAGEDCHAPTYLPAEVDGDVKLSSNLVILPGQDLQYVLATYDTSRVEHAVVY 540 A YVYSPGRSFSYFYPFRLPIKGVPIELQVECFTWDQKLWCRHFCVLADSESGGHITHSGMV 600 B YVYSPGRSFSYFYPFRLPIKGVPIELQVECFTWDQKLWCRHFCVLADSESGGHITHSGMV 600 A GMGVSCTVTREDGTNRR 617 B GMGVSCTVTREDGTNRR 617 † Measles virus hemagglutinin from (A) vaccine and (B) wild strains. be considered [1–5] . other infections) need to expansion and restore the functioning of immu. That is. Measles virus hemagglutinin amino acid sequence from Edmonston vaccine and wild strains: conservation of the epitope sharing with immunodeficiency-related antigens. that the factors at play in the modulation of given these caveats. For example. again it has to be stressed MV-induced immunosuppression [6–18] . signaling lym. Likewise. ‡ Primary measles virus hemagglutinin sequences were aligned using CLUSTAL 2. 510 Future Microbiol. and a single aa change in the H ●●Searching for an anti-MV vaccine: MVH protein (namely. the not yet clear the formulation of anti-MV vaccines based on Table 2. numerous aspect of the observations offered in the above factors appear to be involved in determining the discussion. with a progressive disappearance of viral versus human crossreactivity potential and the immunosuppression status. the concomitant factors that contemporaneously. As mentioned earlier in this paper. the high level months [19] . N481Y) may alter its ability to identity spots at the pentapeptide level bind CD46 [71] . (2015) 10(4) future science group . the vast pentapeptide over- MV-induced immune responses form a complex lap between MVH-derived epitopes and immu- picture. infected individuals. which would allow MV-specific lymphocyte (e..g. it has to be mentioned that nodeficiency-related antigens warrants further there is an association of CD46.

¶ 10  AFYKD  25  INREH  28  EHLMI  32  IDRPY  34  RPYVL  136  LTWCI  137  TWCIN  138  WCINP  226  GMYGG  248  QLSMY  251  MYRVF  268  PVFHM  269  VFHMT  270  FHMTN  271  HMTNY  274  NYLEQ  308  IPYQG  326  VWKSP  332  DMQSW  361  NQAKW  370  TRTDD  378  METCF  384  QACKG  398  EWAPL  440  GMDLY  444  YKSNH  445  KSNHN  449  NNVYW  450  NVYWL  453  WLTIP  472  WIPRF  473  IPRFK  491  GEDCH  526  LATYD  539  VYYVY  555  FRLPI  567  QVECF  569  ECFTW  570  CFTWD  575  QKLWC  578  WCRHF  581  HFCVL † Measles virus hemagglutinin pentapeptides from Edmonston vaccine and wild strains were analyzed for matches in the human proteome using PIR peptide match program [39. ¶ Consecutively overlapping pentapeptides and related amino acid positions given in bold.¶ Pentapeptide§. Indeed.futuremedicine. and have no future science group www. MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  Research Article Table 3. ‡ Pos: Amino acid position in the measles virus hemagglutinin primary sequence. peptides unique to the virus and absent in the entire human proteome highlights that 42 penta- human host.† Amino acid position‡.65]. Pentapeptides uniquely owned by measles virus hemagglutinin and absent in the human proteome. § Pentapeptide: amino acid sequence given in one-letter code. a pentapeptide matching peptides are unique to the viral protein from both analysis of MVH primary sequence versus the Edmonston vaccine and wild strains.com 511 .

Replacing entire antigens from infectious agents with specific peptides unique to the antigens would reduce the potential crossreactivity risk. ●● This paper describes a vast peptide platform shared between MV hemagglutinin derived epitopes and human proteins associated with immunodeficiency. Table 3. molecules crucially involved in the host immune lap. theoretically. 512 Future Microbiol. Conclusion tides might guarantee a high anti-MV specific. NNVYWL. and delineates cross-reactivity as a might be particularly useful in anti-MV vaccine molecular mechanism able to explain the still formulations (i.Research Article Kanduc counterparts in the human proteins. aa sequences data not only offer a key to understanding the in bold). ●● According to CDC [77]. thus suggesting that peptide crossreactivity might be a factor contributing to the establishment of the immunosuppression status. often fatal. thus forming longer peptide stretches that function. The present study describes a wide peptide ity and. PVFHMTNY. The YKSNHN. obscure MV-induced immunosuppression. Indeed. control the collateral adverse events. a viral respiratory disease that is highly contagious and highly widespread. Interestingly. at the same time.76] . The clinical problem ●● Vaccines are available against measles. the success of the MV vaccine is a datum of fact in Western countries only. instead a response crossreacting with self molecules (such as B. thus also allowing repeated and multiple human immunodeficiency-associated pro- vaccinations in order to render permanent the teins. with 20 million cases and 164. no crossreactivity in vac. the peptide uniqueness concept might be applied to define a proper vaccinology for the numerous (re)emerging infectious diseases. as well. confer effectiveness to vaccination. ●● However. advances the hypothesis that immune anti-MV immunization status.000 deaths each year worldwide. MV is still a common and often fatal disease in developing countries. also cause a transient immunosuppression status that can lead to secondary. sharing between MVH-derived epitopes and cinees. Future perspective ●● The present study offers a key to understand the immunosuppression associated with MV infection/vaccination and proposes a methodology to construct safe and effective vaccines against MV. ●● A tight vaccination coverage is necessary and new anti-MV vaccine strategies not potentially burdened by possible collateral immunosuppressive effects are needed.and T-cell antigens.. This set of of measles might be at hand [72–74] without the unique peptide motifs represents the molecular toll of adverse collateral events [75. ●● The peptide commonality between MV hemagglutinin derived epitopes and human proteins associated with immunodeficiency might help understand how immunosuppression is caused by MV and might help design new anti-MV immunotherapies based on peptides unique to MV and not shared with proteins of the human host. Perhaps the goal of global eradication adverse events associated with MV infection and Executive summary The scientific problem ●● Powerful anti-measles virus (MV) immune responses follow MV infection and evoke a lifelong immunity. More in general. a responses against MV may cross-react with few unique pentapeptides consecutively over. and.e. LTWCINP. while anti-MV antibodies pertain to the protective action of the immune system (so that they must be preserved and can last lifelong). (2015) 10(4) future science group . complement proteins and other immunodeficiency-related proteins) breaks immunotolerance mechanisms and must be deleted in the short-long term (weeks to months). signature of MVH and is described in Table 3. ●● Crossreactivity might explain why anti-MV antibodies are present lifelong whereas immune suppression is only transient. In a future perspective. and. ●● The molecular mechanism(s) underlying the immunoprotective and immunosuppressive aspects of anti-MV immune response remain obscure. Possibly vaccines based on such unique pep. infections. the present study represents a viable way for the global eradication of infectious diseases.

228–231 (1996). USA 93(23). 15 Mühlebach MD. Lucchese A. 18 Avota E. 328–334 (2010). honoraria. Pan CH. Lucchese G. Adherens junction protein nectin-4 is the sharing between Influenza A H1N1 Kämpgen E. 87(Pt 10). for investigations involving human subjects. Cell. Schneider-Schaulies S. The results exposed here may lead to the devel. (1996). Physiol. 10 Servet-Delprat C. measles virus infection interferes with for enhancement of viral uptake in dendritic Berlin. differentiation of CD40 ligand-activated 20 Natale C. Bausinger H from the macaque model. Takeda M. 22 Trost B. This includes safe and effective vaccines against MV. Immunol. Schneider-Schaulies J. Nature 406(6798). proteins. Computer-assisted analysis of molecular 3 Schneider-Schaulies S. Med. Schneider-Schaulies S. 330. 20–26 (2014). Richardson CD. sequences. hemagglutinin and human axon guidance Schaulies S. Kanduc D. immunosuppression. and persistence. immunmodulation. Pandey M. Germany. bypass the protective antiviral immune Trends Microbiol. Stufano A. 8(8). 36(3). PLoS Pathog. expert testimony.com 513 . 1 Borrow P. Biochem. PLoS Self Nonself 1(4). Immunol. employment. e1001290 (2011). et al. Ono N. Kusalik from effectors to mechanisms. 580–585 (2000). immunization with Trypanosoma cruzi future science group www. Natl Acad. In: Polymicrobial Diseases. 13194–13199. SLAM (CDw150) is a cellular receptor for A. Gassert E. 24 Lucchese G. Brogden KA. 243–269 11 Yanagi Y. Gen. peptides unique to MV antigens. 8530–8540 (2006). Measles virus induces abnormal e1002885 (2012). epithelial receptor for measles virus. cellular receptors. Gulbins E. (2000). Such vaccines would confer effectiveness to vaccination. 20(9). J. 429–439 (2012). Ohno S. Proc. The author has no relevant affiliations or financial involve. 227–237 measles virus. 245–261 (2010). In: 9 Naniche O. induces immunosuppression in vitro. 5326–5331 (1997). Immunoglobulin G antibody-mediated 14 Noyce RS. Kanduc human dendritic cells. Daniels MD. Oldstone MBA. ASM Press. Schneider-Schaulies S. MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  Research Article anti-MV vaccination protocols. Measles virus-induced immunosuppression: 12 Tatsuo H. (2014). J. 40(2). In addi- Financial & competing interests disclosure tion. Stufano A. lymphocytes and dendritic cells during exempt from bacterial motifs. Wahl LM et al. Yeh A. USA. Tanaka K. Sci. References 8 Karp CL. not even one. 1755–1766 (2008). 164(4). response. 2767–2779 (2006). Ludlow M. Proc. informed consent has been obtained from the participants ment with any organization or entity with a financial involved. de Witte L et al. No writing assistance was utilized in the production of opment of anti-MV vaccines based on specific this manuscript. 4 Avota E. Schnorr JJ. McQuaid S. Griesmann Pathog. Oldstone MBA. PLoS Pathog. FEMS Predominant infection of CD150+ Kusalik A. Xanthakos S. H5N1 and Homo sapiens proteomes. stock ownership or options. ter Meulen V.futuremedicine. 362–375 human blood dendritic cell precursors by 16 Schlender J. Bickis M. elimi. Measles virus. Fujinami RS. measles virus infection of macaques. Peptides 29(10). Virol. Immunol. Schizophr. Biologics 4. Giannini T. Springer. immune control. Yanagi Y. Wysocka M. Curr. Billeter MA (Eds). 21 Kanduc D. consultancies. Massive peptide sharing between viral and Microbiol. 23 Kanduc D. Eta OS. Lin WH. 80(17). Wang K. 85–100 (1995). Manchester M. 5 Griffin DE. 530–533 (2011). No human protein is Microbiol. Washington. 6 Iankov ID. grants or patents received or Future perspective pending. Science 273(5272). Describing the hexapeptide GE. measles virus is associated with Interaction of measles virus with the surface of 25 Leon JS. uninfected peripheral blood lymphocytes Engman DM. Sci. Measles immune suppression: lessons immunosuppression. 3(11). Measles virus-mononuclear cell interactions. or royalties. 7478–7484 19 de Vries RD. J. Measles virus: E7 oncoprotein and human protein (2009). 74(16). J. (2002). Induction of maturation of Nature 480 (7378). Kanduc D. 649–662 (2012). Ethical conduct of research nate the potential cross-reactivity risk. Mateo M. Federspiel MJ. and allow The author states that they have obtained appropriate repeated and safe vaccination campaigns. Schneider. thus institutional review board approval or have followed the providing a viable way for the eradication of MV. production. induction of alpha/beta interferon cells. 199(3). Capone G. Bull. 893–897 human proteomes. 78(6). e178 (2007). Nectin 4 is the identity platform between the influenza A enhancement of measles virus infection can epithelial cell receptor for measles virus. Rev. 17 Avota E. Virol. 1753–1760 (2000) mimicry between human papillomavirus 16 Measles virus-induced immunosuppression. Biol. Guthmiller JM (Eds). A cardiac myosin-specific USA 94(10). 13 de Swart RL. Keikavoussi P. ter host defenses by measles virus: wildtype activation and ceramide generation is essential Meulen V. tropism and pathogenesis. Toriello KM. (2010). DC. 7(2). Vidalain PO. 377–388 et al. Current Topics of Microbiology and Friedman RM. Russell SJ. principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. 34(1). Lucchese G. Microbiol. Peptide 7 Schnorr JJ. Natl autoimmune response is induced by Acad. Spielhoffer P et al. The role of Papers of special note have been highlighted as: Mechanism of suppression of cell-mediated sphingomyelin breakdown in measles virus •• of considerable interest immunity by measles virus. but also propose interest in or financial conflict with the subject matter or peptide uniqueness as a concept for developing materials discussed in the manuscript. Harvey M. Top. Virol. Immunol. D. van Amerongen G 2 Libbey JE. Cell. Virus-induced (2000). Sinn PL et al. Evasion of DC-SIGN mediated sphingomyelinase- Immunology: Measles Virus (Volume 191).

Med. J. Schroeder T. Gen. 345–347 (2003). Resource. Hollenbaugh D human proteins can affect vaccine efficacy. 8(8). Immunol. •• An example of a crossreactive immune www. and flanking residues. Rev. muscle nicotinic acetylcholine receptors. 291–300 NJ. Exp. A.uniprot. commonality between pathogen antigens and 44 Müller CP. Immune UH. Princeton University Press. components. Rice PA. K+-adenosine triphosphatase 52 Patterson JB.Research Article Kanduc proteins. Koszinowski response between a pathogen and the human 38 Kim Y. 39 The UniProt Consortium. (2011). Ponomarenko J. 111–120 (2013). 4. 87(1). required for CD46 interaction. Hernandez M. Nature 337(6208). 56 Dobbs AK. 31(1). Recognition of core and flanking diarrhea. which determines the Gahl WA. J. Biomed. patients who have undergone splenectomy. Yang T. Nucleic Yilma T. dissection of MelanA/ MART-1 oncoprotein Positive measles serology and new onset of 36 de Swart RL. Farmer D. low-similarity peptide vaccines against •• Describes a potential correlation between J. 832341 (2010). 463–471 (1993).ebi. rheumatic fever.iedb. Biosci. Ito Y. Activities at the in human gastric autoimmunity. Peptides 25(11). Aguilar RC. Polat B. 408–416 (2012). functional studies of the measles virus hemagglutinin: identification of a novel site 27 Cunningham MW. Annu. 42(1). similarity. Analysis 55 Aruffo A. Effect of 29 Kanduc D. Infect. Taylor WR. Kaisaki PJ. Curr. 204. J. residues necessary for clonally specific 59 Marion E. 3410–3417 37 Immune Epitope Database and Analysis by the T-cell receptor.  2510–2520 (2002). Dis. characterization of measles virus envelope (1991). (1989). 1147–1156 (2003). 9. Rota PA. hemagglutinin. Askonas BA. (1993). paralysis: a case report. defect in B cell development. 42 Bankamp B. 47 Rothbard JB. Virol. 41 Wu CH. severe combined immunodeficiency. 527–565 mutation in the CD8 alpha gene. The Protein 53 Ram S. a patient with immunodeficiency and a leaky functional units in cell biology and specific antibodies? J. Appelmelk BJ et al. Pentapeptides as minimal immune selection of MV by H protein. Med. 2010. Gen. 1821–1828 (2003). 514 Future Microbiol.org  51 Reddehase MJ. of the neutralizing antibody response to the et al. Molecular mimicry between Helicobacter pylori antigens and H+. 61 Fabre A. is a candidate for type 2 diabetes in rat neutralizing epitopes of measles virus and man. Yüksel S. Charroux B. Rev. Acids Res. 651–653 26 Amedei A. 79(17). Robinson E. Pept. 2012–2017 (2002). 14(2). antigenicity. •• Demonstrates that measles virus Biotechnol. 2055–2059 (2007). Brindley MA et al. Martinez-Vinson C neutralizing antibodies are mainly directed 50 Sant’Angelo DB. Zhang Y.uk/Tools/msa/clustalw2  J. Cell 72(2). gene INPPL1. 11547–11551 (2005). Simon AJ. Universal Protein Resource (UniProt). 43 ClustalW2. Braz. J. SKIV2L mutations cause syndromic to the measles virus (MV) hemagglutinin Denzin LK. J. www. Myasthenogenicity of the Information Resource. Curr. Pouillon V et al. against emerging measles viruses (MVs): hypomorphic mutation in Igbeta (CD79b) in 32 Kanduc D. 40. anti-MV immune responses and diabetes. Kanduc D. Immun. specific contacts. 38(5). 179(4). 23(4). N. 65(2). Gen. 117–123 (2001). Xu W. Immunol. Dis. Structural and 198(8). 349(19). (2004). Cutting edge: a Sci. amino acids of MHC class II-bound peptides Am. Mol. Niewiesk S. Janeway CA Jr. Lewis LA. Virol. immunology. Farrington M. Clin. between immunogenic peptides and MHC et al. J. J. syndrome due to mutations in the beta 3A in mice from the haemagglutinin glycoprotein subunit of the AP-3 adaptor. Infect. 90(4). Kager L. 72(6). haemagglutinin protein. Identification of 2549–2557 (1993). Zhu Z et al. Gefter ML. Yeh LS. Peptide crossreactivity: the vaccine strains. 2321–2328 (1989). 191–198 (2014). 487–494 (2012). 666–675 (2013). Altered trafficking 34 Obeid OE. J. 689–692 (2012). Protein Pept. 74(12).and fusion protein-specific 16(3). J. J. J. Rheumatol. Roifman CM. protein. of measles virus. Bergman MP. Virol. 24(4). 18(8). 1865–1871 type 1 diabetes presented with bilateral facial Relative contributions of measles virus (2004). 11–21 (1999). Immunol. Steward MW. Infections of 28 Luo J. 49 Lucchese G. Computational peptide 60 Onal ED. into a central core. Lucchese A. Mittelman hemagglutinin protein. recognition of a cytotoxic T-cell determinant. Norrby E. Lindstrom J. 245–252 (2012). Front. Manchester M. A pentapeptide as minimal antigenic host. encoding the lipid phosphatase Functional and structural characterization of EMBO J. hyper-IgM syndrome. The 35 Tahara M. Oldstone MB. (1984). Diabetes 51(7). Gen. Sci. Geliebter J. is defective in 30 Frank SA. Familial CD8 deficiency due to a Purification. Kaya G et al. USA (2002). S533–S548 CD3delta deficiency on maturation of alpha/ original sin of vaccines. The CD40 ligand. Rothbard JB. 305–306 (2012). in peptide epitope immunodefinition. beta and gamma/delta T-cell lineages in 1393–1401 (2012). lymphocytes. Probing neutralizing-antibody responses Parolini O. Cell 3(1). Immunol. Proposing serum antibodies to virus neutralization. Takeda M. J. Osterhaus AD. 108(1). Partidos CD. Homology. epitope database analysis resource. Genetic characterization of measles 54 Dadi HK. Virol. Hum. (2015) 10(4) future science group . 86(Pt 2). 48 Tiwari R. Immunology and Evolution of measles virus using synthetic peptides of the activated T cells from patients with X-linked Infectious Diseases. Engl. Stufano A. of lysosomal proteins in Hermansky-Pudlak Identification of helper T cell antigenic sites which determine the binding potential. Shotelersuk V. Kanduc D. SHIP2.ac. 740–780 (2010). Balkan F. Ordi J 33 Varsanyi TM. et al. Utter G. morphology and antigenic proteins. Virol. J. Huang H et al. •• A powerful tool to analyze epitopic peptides. Pemberton RM. Interactions 57 de la Calle-Martin O. Eur. Streptococcus and 40 UniProt. •• Describes how and why the peptide www. Clin. Tu R et al. Scheiflinger F. 365–374 (2005). Nucleic Acids people with complement deficiencies and main immunogenic region and endogenous Res. 142–151 (1999). Bodmer HC. Conley ME. Heider A et al. Opin. Bonifacino JS. Invest. or trichohepatoenteric syndrome. W525–W530 (2012). 46 Rothbard JB. gp39. Mycobacterium tuberculosis. Genet. Scand. 32(9). 31 Kanduc D.org  Virology 256(1). Infect. 355–366 •• Defines the structuration of T-cell epitopes 58 Dell’Angelica EC. Nucleic determinant for MHC class I-restricted T Acids Res. and identity 45 Santibanez S. Microbiol. Autoimmunity 45(3).

Selin LK. Garrison LP Jr et al. Strebel P. Vaccine-induced measles 54–61 (2011). 135–142 SL. constraining factors.jsp  Expert Opin. 15(28). 123–130 (2004). Acquir. Leslie AJ et al. Bentwich Z. Hutchins SS. Cell. 2905–2916 of the entire genomes of B95a cell-isolated HIV infection. Weisman Z. T cell responses. lineage. Burgess C. Pan CH. The association of CD46. Dabbagh A. Comparison of memory. Epitopic peptides with low 65 Peptide match form.. 81(1). Protein information similarity to the host proteome: towards 70 Ovsyannikova IG. Virol. O’Byrne MM. and 73 Keegan R. Dis. Hum.html   434–438 (2007). 77 CDC. Infect. Borkow G. Wang HP. immune suppression.futuremedicine. Sarangi F.  load in chronic human immunodeficiency examination of novel polymorphisms.cdc. T-cell responses is inversely related to viral immune responses: a replication study and 3283–3289 (2009). Cochi Sidhu MS. Comparative nucleotide sequence analyses viral load with CD4 T-cell decline during marmoset B cells. 204(S1). epidemiologic and economic evaluation. Des. eradication programs: enabling and virus strains in the Edmonston vaccine 69 Lin WH. Vierkant RA. Virus Genes 20(3). MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens  Research Article 62 Takeuchi K. 72 Moss WJ. •• A clear picture of the MV infection in terms amino acid change in the hemagglutinin Kalinkovich A. during measles infection. 206–223 (2011). 204(S1). Jacobson RM.gov/measles/about/overview. SLAM 66 Day CL. Comparing measles with previous predicted amino acid sequences of measles (1995). Infect. Adams RJ. “Self-nonself ” peptides in the Proliferative capacity of epitope-specific CD8 variations in measles vaccine-induced design of vaccines. 9(1). J. 27(4). 98–106 (2011). Pharm. I. Walpita P. incidence and associated protein of measles virus determines its ability pathologies. J. A single 67 Leng Q. Iorio C et al. 389–397 (2001). Role of measles eradication. 75 Kanduc D. J. 59(2). 45–53 (2009). Thomas A. Miyajima N. Laube BL. years after vaccination. Tashiro activation correlates better than HIV plasma to bind CD46 and reveals another receptor on M. www. future science group www. Stein M. Dis. J. Ther. Haralambieva IH. 72(4). Dis. Dis. 63 Parks CL. Infect. Lerch RA.bioinformatics. Biochem.   virus type 1 infection. Immune of epidemiology. Poland GA. http://research. (1998). 75(2). •• Describes the role of MV-specific T cells J. Kiepiela P. 910–920 (2001). Virol. J. 253–257 68 Welsh RM. Redd SC. apoptosis in the regulation of virus-induced 47–53 (2011). resource. Udem SA. Hered. J. Strebel PM. Bellini WJ. Razvi ES. and vero cell-isolated measles viruses from the Syndr. Kobune F. J. Biological feasibility of same patient. e01047 (2014). Curr. 71 Hsu EC. edu/peptidematch/index. 72(3). 64 Dine MS. J. and CD209 cellular receptor gene SNPs with 76 Kanduc D.com 515 . mBio 5(2). Virol. (2000). 189(S1). Measles overview. Williams virus-specific T cells do not prevent infection 74 Levin A. Biol. Infect.udel. biological therapies without side effects. Immune Defic. Griffin DE. Persistence of or disease but facilitate subsequent clearance Global eradication of measles: an vaccine-induced antibody to measles 26–33 of viral RNA. 204(S1).