Research Article

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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[13] . 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[15] . 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[1115] . In addition, it is known that the
complex of MV fusion (F) and H glycoproteins induces immunosuppression invitro[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), 503515 ISSN 1746-0913 503
Research ArticleKanduc
that anti-MV antibodies (Abs) are present life-
long, whereas immune suppression is only tran-
sient. With respect to this point, de Swarts lab[19]
performed in vivo studies in macaques and found
that following initial MV-induced lymphopenia,
lymphocyte counts rapidly return to normal after
clearance of the virus, thus posing the question of
why immune suppression then lasts several weeks
to months. The authors concluded that MV
infection wipes out immunological memory, leav-
ing individuals susceptible to opportunistic infec-
tious agents that would normally be controlled by
the immune system[19] . Overall, it appears that
measles-associated immunosuppression is a mul-
tifactorial phenomenon with an immune response
that is diversified and dislocated intime.
In the present study, the potential role of viral
versus human immune crossreactivity was ana-
lyzed. Since 2000, reports from this lab have
described a massive peptide sharing between
microbial and human proteins[2024] . The
data suggested that peptide crossreactivity may
underlie the pathological nexus between the
human host and infectious agents. Indeed, when
bacterial/viral agents share epitopic sequences
with host proteins, an immune response against
the pathogen may result in humoral and/or cel-
lular crossreactions able to hit and damage the
host components[2529] . Actually the crossreac-
tivity scenario is of extreme relevance in light of
two factors: first, the dimension of the peptide
sharing between pathogens and the human pro-
teome (>90%)[21,22] and, second, the notion that
a 5-amino acid grouping plays a basic role in
antigen-antibody recognition and in humoral/
cellular immune reactivity[3032] . Indeed, the
massive pathogen versus human pentapeptide
overlap and the fact that a pentapeptide is suf-
ficient to evoke an immune response mean that
immune reactions following infections may be
a considerable source of crossreactions.
In this scientific framework, the present study
poses the question: may MV versus human pep-
tide overlap represent a link between immune
response and immunosuppression in MV
infection? Since protective anti-MV immune
responses and pathologic immunosuppression
are temporally related following MV infec-
tion[17] , it seemed logical to hypothesize that
viral epitopic sequences targeted by the immune
system might contain the key to understand the
MV infection-induced immunosuppression.
Following this rationale, experimentally vali-
dated epitopes from MV hemagglutinin (MVH)
504 Future Microbiol. (2015) 10(4)
a well-known antigenic and immunogenic
MV protein[3336] have been here explored
for pentapeptide sharing with human proteins
associated with immunodeficiency. Data are
reported showing that MVH-derived epitopes
are mostly formed by peptide fragments also pre-
sent in human proteins associated with immuno-
deficiency and immune system, thus suggesting
that MVH-derived epitopes have the potential
to induce crossreactions with human proteins
involved in immune system functions.
Methods
The analyzed MVH-derived epitopes were
retrieved from the Immune Epitope Database
(IEDB [37]) [38] . At the time of the analysis,
IEDB contained 174 MVH-derived epitopes
from different strains and with different char-
acteristics. Specifically, the database contained
MVH epitopes linear or conformational in the
structure; of different lengths (up to 32 amino
acids [aa]); validated as negative, positive or
had produced mixed negative/positive results
in immunoassays; validated in different hosts.
This study focused on linear epitopes that were
derived from MVH protein (UniProtKB/Swiss-
Prot entry: Q9IC33_MEASZ, 617aa)[39] from
strain EdmonstonZagreb vaccine (or subacute
sclerose panencephalitis virus, NCBI Taxonomic
identifier: 70149); that were not longer than 15
aa; and that had been experimentally tested
as positive in the human host. Based on these
selection criteria, 73 MVH-derived epitopes
were found and analyzed. Each epitope was dis-
sected into overlapping pentapeptides offset by
one residue each other (i.e.,MSPQR, SPQRD,
PQRDR, QRDRI and RDRIN, among others).
Next, each viral pentamer was analyzed for
occurrence(s) within a library containing pri-
mary sequences of human proteins involved in
immune functions and immunodeficiency. The
human protein library was randomly derived
from UniProtKB Database[39,40] , utilizing
immune system, immunodeficiency and Homo
sapiens as keywords. The keyword-guided search
produced a list of 1793 proteins that are syntheti-
cally described in Supplementary Table 1 (see online
at www.futuremedicine.com/doi/suppl/10.2217/
fmb.14.137). Human proteins are reported as
UniProtKB/Swiss-Prot entry names throughout
the paper, unless when discussed in detail.
To identify peptide motifs unique to MVH
protein, each MVH pentapeptide was used as a
probe to search the entire human proteome for
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 MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens
instances of the same pentapeptide using the
Protein International Resource (PIR) peptide
match program[41] . MVH pentapeptides with no
matches to the human proteome were recorded.
MVH protein from Edmonston wild strain,
AF266288.2, NCBI Taxonomic identifier
11234[42] was used as a control in comparative
sequence similarity analyses. Sequence align-
ment of MVH protein from Edmonston vaccine
strain and the wild one was carried out by using
ClustalW2 program[43] .
Results & discussion
Analysis of the peptide sharing between
MV-derived epitopes and human proteins related
to immunodeficiency was conducted on the viral
H protein since, as indicated by an ample litera-
ture[3336,44,45] , the MVH is a main target of the
humoral immune responses. The analysis used
pentapeptides as scanning probes based on the
validated concept that a grouping of five aa resi-
dues represents a quantum in immunorecogni-
tion and immunoreactivity([31,32] and pertinent
references therein). Indeed, also T-cell epitopes,
canonically represented by peptides 915-aa long,
consist of a core pentapeptide motif, which pro-
vides the majority of the specific contacts, and of
flanking residues, which determine the peptide
binding potential[4651] . A paradigmatic exam-
ple of the crucial role exerted by small peptide
modules in MV immunobiology is the MVH
pentapeptide IPRFK (aa position 473477) that
constitutes an epitope recognized by the anti-
MVH MAb E128[35] . Moreover, MVH protein
entirely lost its reactivity with MAb E128 when
carrying aa substitutions at positions 473 to 477
and the same pentapeptide region is involved in
the interaction with CD46, a receptor for MV
vaccine strains[52] .
The overall picture of the pentapeptide overlap
between MVH-derived epitopes and immunode-
ficiency-associated proteins is reported in Table 1.
It can be seen that, numerically, 219 human pro-
teins involved in the modulation and regulation
of immune functions share peptide sequences
with B- and T-cell MVH-derived epitopes.
Description of the potential peptide
crossreactome between MVH
&immunodeficiency-associated proteins
A first, immediate datum that emerges from the
analysis of Table 1 is that only six out of the selected
73 MVH epitopes are exempt from pentapeptide
matches with the immunodeficiency-associated
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Research Article
proteins. The remaining 67 viral epitopes share
peptides with human proteins crucially involved
in the human defense system as complement pro-
teins CO2, CO3, and CO6. Obviously, an anti-
MVH immune response crossreacting with CO2,
CO3 and CO6 might lead to deficiencies of such
complement proteins, thus predisposing individ-
uals to recurrent respiratory infections and infec-
tions caused by encapsulated organisms including
Streptococcus pneumonia [53] . In addition, Table 1
shows that the peptide sharing involves cluster
differentiation (CD) antigens associated with
B- and T-cell development and maturation, such
as CD14; CD1C; CD24; CD34; CD36; CD38;
CD3D; CD5L; CD79B; CD8A; CD40L. As
regards this latter potential target of crossreac-
tions, CD40L, it is of note to recall that abnormal
differentiation of CD40 ligand-activated human
DCs is induced by MV[10] .
Clinically, alterations in these CD molecules
have been involved in: immunodeficiency with
impairment of both humoral and cell-mediated
immunity, and consequent persistent infec-
tions by opportunistic organisms (CD3D)[54] ;
recurrent bacterial and opportunistic infections,
including Pneumocystis carinii pneumonia and
intractable diarrhea due to Cryptosporidium infec-
tion (CD40L)[55] ; agammaglobulinemia with
consequent severe infections in the first years of
life (CD79B)[56] ; immunologic defect leading to
recurrent bacterial infections (CD8A)[57] .
In the scientific context of the present study,
the peptide sharing between MVH and the CD
antigens described above also offers a chance to
observe that CD molecules are spatially located
on the surface of B or T cells, thus being highly
accessible to crossreactive attacks; in other
words, might de facto represent privileged targets
in immune crossreactions.
Table 1 also shows that, in many instances, the
peptide overlap is multiple. For example:
AP3B1 shares pentapeptides DSESG, SLLDL
and TVELK (with SLLDL and TVELK
repeated twice) with five MVH-derived B-cell
epitopes (see Table 1, IEDB IDs 42603, 39483,
23048, 39732 and 7279). Altered AP3B1 is
involved in an increased susceptibility to
infections[58] ;
SHIP2 shares pentapeptides AAEEL and
FEVGV with three B-cell epitopes (IEDB IDs
9929, 73483 and 56283) and one T-cell epitope
(IEDB ID 59787) for a total of four matches.
Alterations of SHIP2 are involved in
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Table 1. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency.
Position IEDB ID Epitope sequence, Epitope immune context# Human immunodeficiency proteins sharing peptides with MVH,,,
1 42622 mspqrdrinaFYKDN T cell, HLA-class II DOCK2 (FYKDN)
29 24256 hlmidrpyv T cell, HLA-A*02:01
30 38042 lmidrpyvl MHC binding; T cell, HLA-A2,
HLA-A*02:01
31 41693 midrPYVLLAVLFVm B cell; 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, HLA-A2 IRAK3 (VMFLSL) PRL (FLSLI)
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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-A2 PDIA3 (FISDK) CATE (SDKIK) PPARG (DKIKF)

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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, AAEEL) SHIP2 (AAEEL) PDC6I (AAEEL) DAB2P (AAEEL)
M3K14 (AEELM) NCOA1 (EELMN)
153 73483 YCADVAAEELMNALV B cell RAE1L (YCADV, 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.

Epitope IEDB ID from[37].

Amino acid sequence given in one-letter code.

Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals.
#
Further data and related references from[37].

Proteins given by UniProtKB/Swiss-Prot entry names.

In parentheses, shared pentapeptide(s) given in italic.

Proteins sharing two overlapped pentapeptides (e.g.,a hexapeptide) are given in bold.

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Proteins sharing two pentapeptides are given underlined.
IEDB: Immune Epitope Database ; MVH: Measles virus hemagglutinin.
 Table 1. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency (cont.).
Position IEDB ID Epitope sequence, 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

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(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, T cell, HLA-A2, 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)

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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.

Epitope IEDB ID from[37].

Amino acid sequence given in one-letter code.

Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals.
#
Further data and related references from[37].

Proteins given by UniProtKB/Swiss-Prot entry names.

In parentheses, shared pentapeptide(s) given in italic.

Proteins sharing two overlapped pentapeptides (e.g.,a hexapeptide) are given in bold.

Proteins sharing two pentapeptides are given underlined.
IEDB: Immune Epitope Database ; MVH: Measles virus hemagglutinin.
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Table 1. Peptide sharing between measles virus hemagglutinin-derived epitopes and human proteins associated with immunodeficiency (cont.).
Position IEDB ID Epitope sequence, Epitope immune context# Human immunodeficiency proteins sharing peptides with MVH,,,
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, ALGVI) ZEP2 (LTIPP) NCKP1 (KNLAL) RPC2 (KNLAL) UBA3 (KNLAL) RAD50 (NLALG)
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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, 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)

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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, 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; T cell, HLA-A2,
HLA-A*02:01
576 32242 klwcrhfcvl T cell, HLA-A2
583 7279 cVLADSESGGHIThs B cell I10R2 (VLADS, 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.

Epitope IEDB ID from[37].

Amino acid sequence given in one-letter code.

Pentapeptide sequence(s) shared with the human proteins associated with immunodeficiency given in capitals.
#
Further data and related references from[37].

Proteins given by UniProtKB/Swiss-Prot entry names.

In parentheses, shared pentapeptide(s) given in italic.

Proteins sharing two overlapped pentapeptides (e.g.,a hexapeptide) are given in bold.

future science group

Proteins sharing two pentapeptides are given underlined.
IEDB: Immune Epitope Database ; MVH: Measles virus hemagglutinin.
 MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens
diabetes[59] and might represent a link between
diabetes and anti-MV immune responses[60] ;
SKIV2 has five pentapeptide matches (LGAPV,
LLAVL, LTIPP, plus ALGVI repeated twice)
disseminated through four MVH B-cell
epitopes (IEDB IDs 2598, 41693, 72808, and
47694; one of which, IEDB ID 41693, is also
a T-cell epitope). Alterations in SKIV2 appear
to be involved in a hepatoenteric syndrome
characterized by severe diarrhea in infancy, and
immunodeficiency[61] .
To add complexity to the potential crossreac-
tome, the majority of MVH epitopes share pep-
tides with numerous proteins, thus suggesting
the possibility of multiple crossreactivity. For
example, an immune response directed against
the B-cell epitope KPNLSSKRSELSQLS (see
Table 1, IEDB ID 32807) might potentially
crossreact with 15 crucial proteins related to
the immune function.
MVH from Edmonston vaccine & wild
strains: comparative analysis of the
epitopic peptide sharing
Next, it was investigated whether the epitopic
peptide sharing illustrated in Table 1 was exclu-
sively associated with the measles vaccine strain.
To this aim, as shown in Table 2 , the MVH
Edmonston wild strain[42] was aligned with the
vaccine sequence and searched for the peptide
platform shared with immunodeficiency-related
antigens described above in Table 1.
In agreement with reports showing that vac-
cine viruses differed at most by 0.3% from the
Edmonston wild strain[62,63] , Table 2 illustrates
that only a few aa substitutions (namely 5 aa
changes, see Table 2, residues given bold) differ-
entiate the vaccine strain MVH from the wild
one. Consequential to such a sequence conserva-
tiveness, also the epitope sharing with immuno-
deficiency-related antigens is highly conserved
in the MVH from the Edmonston wild strain
(Table 2, aa sequences given underlined).
The high level of conservation of wild-type
and vaccine MV Edmonston sequences offers
the chance to discuss two main points related to
MV-associated immunosuppression. In primis,
Table 2 might reasonably explain why immuno-
suppression associates with both MV infection
and MV vaccination. Being highly conserved
the epitopic peptide sharing described in Table1,
it appears to be logical that postinfectious and
postvaccination immune responses have similar
future science group
Research Article
immunodeficiency consequences as a common
denominator.
In secundis, the conservativeness of MV wild-
type and vaccine sequences poses the problem of
explaining the much weaker immunosuppression
that follows vaccination. In fact, on one hand,
Table 2 suggests that crossreactivity may well
represent a contributing factor in establishing
immunosuppression following both MV infec-
tion and vaccination; then, on the other hand,
it does not explain the different extent of the
immunosuppression. Actually, given the common
epitopic platform (Tables 1 & 2), one would expect
that MV wild type and vaccine had pathologic
consequences of similar extent. In this regard,
Table 1 suggests a rational explanation. Indeed,
a careful analysis of MVH-derived epitopes
shows that two B-cell epitopes (IEDB ID: 2598,
ALGVINTLEWIPRFK, and IEDB ID: 28041,
IPRFKVSPYLFNVPI) host the pentapeptide
IPRFK that, as recalled above, constitutes an
epitope recognized by the anti-MVH mAb
E128 [35] . This pentapeptide is involved in the
interaction with CD46, a receptor for MV vaccine
strains [52] , so that hitting IPRFK might affect
MV vaccine propagation, reduce the viral load,
and moderate the immune response and the asso-
ciated immunodeficiency phenomenon. In fact,
measles-specific antibody titer after vaccination
is lower than after natural infection[64] .
Moreover, antigen load and lymphopenia have
been found to be inversely related in viral infec-
tions and may correlate with viral clearance or
persistence [6668] so that a decreased viral load
may reboot lymphocyte proliferation[66,67] . In
other words, the anti-MV immune responses that
follow MV infection/vaccination, although bur-
dened by a crossreactive potential that concurs in
establishing lymphopenia, at the same time, may
clear/decrease the viral antigen load, thus posing
the basis for progressively restoring the immune
activity. It seems pertinent to mention that vac-
cine-induced MV-specific Tcells do not appear
to prevent infection or disease but facilitate sub-
sequent clearance of viral RNA [5,69] . Rebooting
lymphocyte proliferation and restoring the
immune activity might also ripristinate the host
immunotolerance mechanisms and progressively
delete B- and T-cell crossreactive responses, even-
tually eliminating the immunosuppression sta-
tus. Hence, crossreactivity appears to be at the
basis of the contradictory sequela of MV-induced
lymphopenia, immediately subsequent massive
expansion of MV-specific lymphocytes, and
www.futuremedicine.com 509
Research ArticleKanduc

immunosuppression lasting several weeks to
months[19] . That is, the most immediate effects
of crossreactivity would be lymphopenia and,
contemporaneously, decrease of the viral antigen
load, which would allow MV-specific lymphocyte
expansion and restore the functioning of immu-
notolerance mechanisms in the course of weeks
to months, with a progressive disappearance of
the immunosuppression status.
It is mandatory to underline the speculative
aspect of the observations offered in the above
discussion. Likewise, again it has to be stressed
that the factors at play in the modulation of
MV-induced immune responses form a complex
picture. For example, it has to be mentioned that
there is an association of CD46, signaling lym-
phocyte activation molecule and CD209 cellular
receptor gene single nucleotide polymorphisms
with variations in MV vaccine-induced immune
responses [70] , and a single aa change in the H
protein (namely, N481Y) may alter its ability to
bind CD46[71] . Moreover, the scientific-clinical
complexity of the MV infection, the not yet clear
aspects of the MV immunology, the high level
of viral load variability that may characterize
infected individuals, the concomitant factors that
may favor the immunodeficienty phenomenon
(e.g.,malnourishment, other infections) need to
be considered[15] . Finally, it has to be noted that
the present MVH analysis is not exhaustive of the
viral versus human crossreactivity potential and
other MV proteins may also play an important
role. As mentioned earlier in this paper, numerous
factors appear to be involved in determining the
MV-induced immunosuppression[618] . However,
given these caveats, the vast pentapeptide over-
lap between MVH-derived epitopes and immu-
nodeficiency-related antigens warrants further
experimental research in order to understand and
define a possible contribution of crossreactivity to
MV-induced immunosuppression.
Searching for an anti-MV vaccine: MVH
identity spots at the pentapeptide level
This study might also offer approaches toward
the formulation of anti-MV vaccines based on

Table 2. Measles virus hemagglutinin amino acid sequence from Edmonston vaccine and wild strains:conservation of the
epitope sharing with immunodeficiency-related antigens.
Strain Location of epitopic sequences,, 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; further details are provided in Methods section.

Primary measles virus hemagglutinin sequences were aligned using CLUSTAL 2.1 sequence alignment program[43].

Sequences relative to the epitopic peptide sharing found with vaccine strain (see Table 1) are underlined.

Amino acid substitutions are given in bold.

510 Future Microbiol. (2015) 10(4) future science group

 MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens Research Article

Table 3. Pentapeptides uniquely owned by measles virus hemagglutinin and absent in the
human proteome.
Amino acid position, Pentapeptide,
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[39,65].

Pos:Amino acid position in the measles virus hemagglutinin primary sequence.

Pentapeptide:amino acid sequence given in one-letter code.

Consecutively overlapping pentapeptides and related amino acid positions given in bold.

peptides unique to the virus and absent in the entire human proteome highlights that 42 penta-
human host. Indeed, a pentapeptide matching peptides are unique to the viral protein from both
analysis of MVH primary sequence versus the Edmonston vaccine and wild strains, and have no

future science group www.futuremedicine.com 511

Research ArticleKanduc

counterparts in the human proteins. This set of
unique peptide motifs represents the molecular
signature of MVH and is described in Table 3.
Possibly vaccines based on such unique pep-
tides might guarantee a high anti-MV specific-
ity and, theoretically, no crossreactivity in vac-
cinees, thus also allowing repeated and multiple
vaccinations in order to render permanent the
anti-MV immunization status. Interestingly, a
few unique pentapeptides consecutively over-
lap, thus forming longer peptide stretches that
might be particularly useful in anti-MV vaccine
formulations (i.e.,LTWCINP, PVFHMTNY,
YKSNHN, NNVYWL; Table 3, aa sequences
in bold). Perhaps the goal of global eradication
of measles might be at hand[7274] without the
toll of adverse collateral events[75,76] .
Conclusion
The present study describes a wide peptide
sharing between MVH-derived epitopes and
human immunodeficiency-associated pro-
teins, advances the hypothesis that immune
responses against MV may cross-react with
molecules crucially involved in the host immune
function, and delineates cross-reactivity as a
molecular mechanism able to explain the still
obscure MV-induced immunosuppression. The
data not only offer a key to understanding the
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, and, at the
same time, also cause a transient immunosuppression status that can lead to secondary, often fatal, infections.
The molecular mechanism(s) underlying the immunoprotective and immunosuppressive aspects of anti-MV immune
response remain obscure.
This paper describes a vast peptide platform shared between MV hemagglutinin derived epitopes and human proteins
associated with immunodeficiency, thus suggesting that peptide crossreactivity might be a factor contributing to the
establishment of the immunosuppression status.
Crossreactivity might explain why anti-MV antibodies are present lifelong whereas immune suppression is only
transient. Indeed, while anti-MV antibodies pertain to the protective action of the immune system (so that they must
be preserved and can last lifelong), instead a response crossreacting with self molecules (such as B- and T-cell antigens,
complement proteins and other immunodeficiency-related proteins) breaks immunotolerance mechanisms and must
be deleted in the short-long term (weeks to months).
The clinical problem
Vaccines are available against measles, a viral respiratory disease that is highly contagious and highly widespread.
However, the success of the MV vaccine is a datum of fact in Western countries only.
According to CDC[77], MV is still a common and often fatal disease in developing countries, with 20 million cases and
164,000 deaths each year worldwide.
A tight vaccination coverage is necessary and new anti-MV vaccine strategies not potentially burdened by possible
collateral immunosuppressive effects are needed.
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.
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. More in general, the peptide uniqueness
concept might be applied to define a proper vaccinology for the numerous (re)emerging infectious diseases. Replacing
entire antigens from infectious agents with specific peptides unique to the antigens would reduce the potential
crossreactivity risk, control the collateral adverse events, and, as well, confer effectiveness to vaccination. In a future
perspective, the present study represents a viable way for the global eradication of infectious diseases.

512 Future Microbiol. (2015) 10(4) future science group

 MVH epitopes are hotspots for crossreactions with human immunodeficiency antigens Research Article

anti-MV vaccination protocols, but also propose
peptide uniqueness as a concept for developing
safe and effective vaccines against MV.
Future perspective
The results exposed here may lead to the devel-
opment of anti-MV vaccines based on specific
peptides unique to MV antigens. Such vaccines
would confer effectiveness to vaccination, elimi-
nate the potential cross-reactivity risk, and allow
repeated and safe vaccination campaigns, thus
providing a viable way for the eradication of MV.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involve-
ment with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
Ethical conduct of research
The author states that they have obtained appropriate
institutional review board approval or have followed the
principles outlined in the Declaration of Helsinki for all
human or animal experimental investigations. In addi-
tion, for investigations involving human subjects,
informed consent has been obtained from the participants
involved.

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