Analysis of herpes simplex virus type 1 restriction fragment length polymorphism variants associated with herpes gladiatorum and Kaposi's varicelliform eruption in sumo wrestlers

Abstract

The geographical distribution of herpes simplex virus type 1 (HSV-1) restriction fragment length polymorphism (RFLP) variants BgK(L) and BgO(L) and the high relative frequency (RF) of BgK(L) in orolabial lesions has led to a dispersion-replacement hypothesis for these variants. The pathogenic properties of HSV-1 variants in mice and professional sumo wrestlers were examined here. The wrestlers herpes gladiatorum (HG) was caused by primary and non-primary HSV-1 infections and recurred in many wrestlers. HSV-1 neutralizing antibody titres in sera from wrestlers who did not develop HG were relatively high. HG was caused by distinct HSV-1 variants and strains from wrestlers living in the same sumo stable. The BgK(L) RF was significantly higher in HG cases, particularly in those with Kaposi's varicelliform eruption. These data indicated that reactivation and transmission of latent HSV-1 infections, especially BgK(L), occurred frequently among wrestlers and was caused by severe skin damage. These results support the BgK(L) dispersion hypothesis.

Full text

Short
Communication
Analysis of herpes simplex virus type 1 restriction
fragment length polymorphism variants associated
with herpes gladiatorum and Kaposi’s varicelliform
eruption in sumo wrestlers
Fumihiko Ban,
1,2
Satoe Asano,
3
Shigeru Ozawa,
4
Hiroyuki Eda,
1
3
James Norman,
5
William G. Stroop
5
and Kazuo Yanagi
1
4
Correspondence
Kazuo Yanagi
kyanagi@nih.go.jp
1
Herpesvirus Laboratory, Department of Virology I, National Institute of Infectious Diseases, Toyama
1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
2
BML General Institute, Matoba 1361-1, Kawagoe, Saitama 350-1101, Japan
3
Department of Dermatology, Doai Kinen Hospital (Fraternity Memorial Hospital, Japan), Yokoami
2-1-11 Sumida-ku, Tokyo 130-8587, Japan
4
Yamanashi Institute of Health, Kofu City, Yamanashi Prefecture, Japan
5
Department of Ophthalmology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030-
3498, USA
Received 21 April 2008
Accepted 10 June 2008
The geographical distribution of herpes simplex virus type 1 (HSV-1) restriction fragment length
polymorphism (RFLP) variants BgK
L
and BgO
L
and the high relative frequency (RF) of BgK
L
in
orolabial lesions has led to a dispersion–replacement hypothesis for these variants. The
pathogenic properties of HSV-1 variants in mice and professional sumo wrestlers were examined
here. The wrestlers herpes gladiatorum (HG) was caused by primary and non-primary HSV-1
infections and recurred in many wrestlers. HSV-1 neutralizing antibody titres in sera from wrestlers
who did not develop HG were relatively high. HG was caused by distinct HSV-1 variants and
strains from wrestlers living in the same sumo stable. The BgK
L
RF was significantly higher in HG
cases, particularly in those with Kaposi’s varicelliform eruption. These data indicated that
reactivation and transmission of latent HSV-1 infections, especially BgK
L
, occurred frequently
among wrestlers and was caused by severe skin damage. These results support the BgK
L
dispersion hypothesis.
Herpes simplex virus type 1 (HSV-1) variant BgK
L
is a
restriction fragment length polymorphism (RFLP) variant
(Ozawa et al., 1988, 1989a) caused by loss of the BglII
cleavage site between the BglII K and Q/13 fragments (Eda
et al., 2007). BgK
L
is a good surrogate marker for the HSV-
1 multiple mutant BgK
L
:SaCFJ
M
:SaE
L
:SaGH
M
:KpM
S
,
where SaCFJ
M
denotes loss of SalI fragments C, F and J,
SaE
L
denotes a larger SalI L fragment, SaGH
M
denotes loss
of SalI G and H fragments and KpM
S
denotes a smaller
KpnI M fragment (Eda et al., 2007; Ozawa et al., 2006). The
prevalence of BgK
L
in HSV-1 clinical isolates, referred to as
its relative frequency (RF), is 27 % in Japan (Ozawa et al.,
2006). Another HSV-1 RFLP variant BgO
L
(Ozawa et al.,
1989b) has lost the BglII cleavage site between the BglII Q/
13 and O fragments (Eda et al., 2007). It has been proposed
that BgK
L
spread and replaced BgO
L
in Japan, based on the
geographical distribution profiles of BgK
L
and BgO
L
(Eda
et al., 2007; Ozawa et al., 1989b, 2006) and the high RF of
BgK
L
in orolabial infections (Ozawa et al., 2007).
In the present study, we compared the pathogenic and
epidemiological properties of HSV-1 BgK
L
, BgO
L
and non-
BgK
L
:non-BgO
L
variants in mice and sumo wrestlers with
herpes gladiatorum (HG). Central nervous system (CNS)
destruction is a major consequence of experimental murine
disease induced by HSV-1 (Dix et al., 1983b; Goel et al.,
2002; Mao & Rosenthal, 2003; Richards et al., 1981;
Roizman & Knipe, 2001). HG has been documented
among wrestlers and rugby players (Anderson, 2003;
Becker, 1992; Belongia et al., 1991; De Bernardo, 1992;
Turbeville et al., 2006; White & Grant-Kels, 1984). HSV-1
isolates from HG cases in professional sumo wrestlers that
3Present address: St Louis Laboratories, Pfizer Inc., 700 Chesterfield
Parkway West, Mail Zone AA3C Chesterfield, MO 63017, USA.
4Present address: AIDS Research Center National Institute of Infectious
Diseases, Toyama 1-23-1, Shinjuku, Tokyo 162-8640, Japan.
Two supplementary figures and data supplements A–K are available
with the online version of this paper.
Journal of General Virology (2008), 89, 2410–2415 DOI 10.1099/vir.0.2008/003368-0
2410 2008/003368 G2008 SGM Printed in Great Britain

were previously described by Asano et al. (1994) were
analysed further because the high HG frequency in these
wrestlers and their traditional lifestyle, in which they live
together in communal and isolated sumo stables, facilitated
studies of HSV-1 epidemiology.
For pathogenicity experiments in mice, the HSV-1 isolates
(and their isolation sites) used were: BgK
L
isolates RM48
(skin), TS9 (gingivostomatitis) and KH424 (keratitis);
BgO
L
isolates RM57 (mouth), Y82-469 (mouth) and
IW30 (lips); and non-BgK
L
:non-BgO
L
isolates RK
[Kaposi’s varicelliform eruption (KVE)], TS5 (lips) and
TS6 (gingivostomatitis). The three non-BgK
L
:non-BgO
L
isolates showed the same RFLP profiles as strain F (kindly
provided by Dr B. Roizman, University of Chicago) with
BglII, SalI, KpnI, BamHI, HindIII, HpaI and EcoRI (Ozawa
et al., 2006). The pathogenicity of HSV-1 clinical isolates
was assayed (Beers et al., 1993, 1995) by inoculating BALB/
c mice with a dilution series of each virus. Each mouse was
injected with a 20 ml virus suspension for intracranial
inoculations and a 100 ml virus suspension for intraper-
itoneal inoculations. Five mice were injected for each HSV-
1 suspension dilution.
Neuroinvasiveness of the clincial isolates in mice was
examined by intraperitoneal inoculation (Supplementary
Fig. S1a, available in JGV Online) and indicated that the
log
10
LD
50
values were: .6.0 (KH424), 3.2 (RM48) and 4.0
(TS9) for BgK
L
(i.e. a .2.8 log LD
50
range); 2.4 (RM57),
4.0 (IW30) and 2.6 (Y82-469) for BgO
L
(i.e. a 1.6 log LD
50
range); and 2.6 (RK), 3.0 (TS6) and .6.0 (TS5) for non-
BgK
L
:non-BgO
L
, (i.e. a .3 log LD
50
range). The neuro-
virulence of the clincial isolates was examined by
intracranial inoculation in mice (Supplementary Fig. S1b)
and indicated that the log
10
LD
50
values were: ,1.0
(KH424), ,1.0 (RM48) and 1.8 (TS9) for BgK
L
;,1.0
(RM57), 1.4 (IW30) and ,1.0 (Y82-469) for BgO
L
; and
,1.0 (RK), ,1.0 (TS6) and 3.8 (TS5) for non-BgK
L
:non-
BgO
L
(i.e. similar log
10
LD
50
values for isolates of the three
variants). These results indicate that the pathogenicity of
BgK
L
isolates in mice, measured as LD
50
values, varied
widely between isolates and was similar to that for BgO
L
and non-BgK
L
:non-BgO
L
isolates and for HSV-1 clinical
isolates (Bergstrom et al., 1990; Dix et al., 1983a, 1983b;
Mao & Rosenthal, 2003; Richards et al., 1981) and mutants
(Roizman & Knipe, 2001).
Clinical specimens and HSV-1 isolates from sumo
wrestlers, described previously by Asano et al. (1994), were
taken between August 1989 and July 1994 from young
professional sumo wrestlers with HG living in eight
different sumo stables in Tokyo: Tomozuna, Takasago,
Oguruma, Nishonoseki, Tatsunami, Kokonoe, Dewanoumi
and Wakamatsu (designated stables B, D, E, G, I, J, K and
L, respectively). Clinical diagnosis was at the Doai Kinen
Hospital (The Fraternity Memorial Hospital). One wrestler
in stable D developed headaches and died 2 months after
clinical diagnosis of HG in 1989 and one wrestler in stable
F was diagnosed with herpes encephalitis in 1990; speci-
mens were not obtained from these two wrestlers, however,
this indicates that HSV-1 infections can be fatal in some
cases and as such they warrant investigation. Specimens
were inoculated into MRC-5 (ATCC, CCL-171) cell
cultures. Thirty-nine sumo wrestlers were diagnosed with
HG; HSV-1 was isolated from 22 of these wrestlers (Asano
et al., 1994) and HSV-2 was isolated from another wrestler
(data not shown). Virus isolates were propagated on Vero
cell (Yasumura & Kawakita, 1988) monolayers and their
HSV type was identified using HSV type-specific mono-
clonal antibodies, with plaque titration performed as
previously described (Yanagi, 1981). The virus suspensions
used in this study were prepared from virus stocks that had
not been passaged more than five times after isolation.
Neutralizing and complement-requiring neutralizing
(CRN) antibodies against HSV-1 in serum specimens were
titrated soon after the specimens were taken, as previously
described (Asano et al., 1994; Yoshino & Abe, 1981;
Yoshino & Isono, 1978). Complement (0.25 units) was
added to each well of 96-well micro-test plates for CRN
antibody titrations (Yoshino & Abe, 1981). RFLP analyses
were performed as previously described (Eda et al., 2007;
Ozawa et al., 2006) using the restriction endonuclease
maps of strain F as references (Hayward et al., 1975; Locker
& Frenkel, 1979; Roizman, 1979; Roizman & Tognon,
Fig. 1. Restriction endonuclease maps of HSV-1 with the
enzymes used in this study. The restriction fragments that showed
polymorphisms in the present report are indicated by large letters.
The asterisks indicate subterminal fragments, the variability of
which was suggested by Roizman & Tognon (1983).
HSV-1 RFLP variants associated with herpes gladiatorum
http://vir.sgmjournals.org 2411

1983). The terminal internal and ‘joint’ sequences contain-
ing the 280 bp repeat, consisting predominantly of the
terminal reiterated sequence ‘a’ (Davison & Wilkie, 1981;
Locker & Frenkel, 1979; Roizman, 1979) (Fig. 1), were
excluded from the RFLP analyses (Locker & Frenkel, 1979;
Roizman & Tognon, 1983; Wagner & Summers, 1978).
Several subterminal fragments with size variability, as
previously described by Roizman & Tognon (1983), are
indicated in Fig. 1.
In HSV infections, CRN antibody against HSV (Mandel,
1978; Yanagi, 1981; Yoshino et al., 1977; Yoshino & Isono,
1978) appears in early immune sera of infected patients
and experimental animals, as described previously
(Yoshino & Isono, 1978; Yoshino & Taniguchi, 1966;
Zheng & Hsiung, 1984), and CRN antibody titres are
higher than neutralizing antibody titres in early sera
(Yoshino & Isono, 1978; Yoshino & Taniguchi, 1966).
Five sumo wrestler HG cases in stable L presented almost
concurrently (Table 1). One HG case (HG37IY) presented 2
weeks later, another (HG38OH) presented 1 month after
HG37IY and another (HG39OY) presented 8 months after
HG38OH (Table 1). Sera from five HG cases obtained before
or at the onset of HG were negative (i.e. titre ,4) for HSV-
1-neutralizing and CRN antibodies. Four of these cases
seroconverted, as determined by their HSV-1-neutralizing
and CRN antibody titres, but paired sera were not obtained
for the fifth case (HG35HH) (Table 1). These data indicated
that these five HG cases were primary HSV-1 infections. In
three other cases from stable L, the HSV-1-neutralizing and
CRN antibodies were positive before or at HG onset/
diagnosis (Table 1), indicating that these cases were not
primary HSV-1 infections. In four cases from stable E (Table
1), HSV-1-neutralizing and CRN antibodies were negative
in two cases (HG24MT and HG25SM) and positive in two
cases (HG15HK and HG16AT) at the time of HG diagnosis,
indicating that the former cases were primary HSV-1
infections and the latter were not. HG recurred in a number
of sumo wrestlers, as described in data supplement A.
Three wrestlers in stable L did not develop HG despite
living and training together with wrestlers with HG. The
sera of these three wrestlers had HSV-1 neutralizing
antibody titres ¢32 and CRN antibody titres ¢128
(Table 1). These neutralizing antibody levels were higher
than those in sera from wrestlers with HG taken before or
at the onset of HG (Table 1).
Five different HSV-1 isolates with distinct RFLP profiles,
namely different HSV-1 strains, were involved in HG cases
in stable L and two were involved in HG cases in stable D. In
Table 1. HSV-1-neutralizing and CRN antibodies in sera
Case HG diagnosis Virus isolation Blood sample Antibody titre Infection
Neutralizing CRN
Sera from stable L sumo wrestlers
HG32KK 19 July 1993 23 July 1993 15 June 1993 ,4,4 Primary
31 July 1993 ,445
HG33TM 23 July 1993 26 July 1993 15 June 1993 16 64 Non-primary (recurrent HG)
17 December 1993 22 (2
4.5
) 128
HG34NM 26 July 1993 26 July 1993 23 July 1993 8 45 (2
5.5
) Non-primary (recurrent HG)
HG35HH 23 July 1993 26 July 1993 26 July 1993 ,4,4 Primary
HG36OK 23 July 1993 23 July 1993 23 July 1993 ,4,4 Primary
31 July 1993 ,464
HG37IY 7 August 1993 8 August 1993 4 August 1993 ,4,4 Primary
20 August 1993 ,44
HG38OH 7 September 1993 7 September 1993 7 September 1993 16 90 Non-primary (recurrent HG)
HG39OY 6 May 1994 6 May 1994 2 August 1993 ,4,4 Primary
6 May 1994 ,411
NHG40NT No onset – 31 July 1993 ¢32 ¢128 Previously infected
NHG41IT No onset – 4 August 1993 ¢32 ¢128 Previously infected
NHG42NM No onset – 4 August 1993 ¢32 ¢128 Previously infected
Sera from stable E sumo wrestlers
HG24MT 15 May 1992 15 May 1992 14 May 1992 ,4,4 Primary (first HG)
12 June 1992 ,4,4
HG25SM 14 May 1992 14 May 1992 14 May 1992 ,4,4 Primary (first HG)
12 June 1992 4 16
HG15HK 11 June 1992 11 June 1992 11 June 1992 8 64 Non-primary (recurrent HG)
17 June 1992 8 45
HG16AT 6 August 1993* 6 August 1993* 31 July 1993 8 22 Non-primary (recurrent HG)
*Of the two viruses isolated from case HG16AT, this is the sampling date for isolation of virus HG16AT-D22 (Table 2).
F. Ban and others
2412 Journal of General Virology 89

Table 2. Characteristics of sumo wrestler herpes gladiatorum (HG) cases and HSV-1 isolates
Stable HG case RF of BgK
L
in wrestler’s
original geographical region*
HSV-1 isolate designation BglII RFLP variant Main lesion site KVE
B HG3MHA Unknown (USA; 21) HG3MHA-D2 BgO
L
Eyelid 2
HG27KH Low (Kyushu; 20) HG27KH-D14 BgO
L
Forehead 2
D HG8TM Lower (Chubu-Tohoku; 16) HG8TM-D3 BgK
L
(D3) Ear +
HG26KY Lower (KantoD; 15) HG26KY-D8 BgK
L
(D8/21) Cheek 2
HG28AK Lower (Kanto; 19) HG28AK-D21 BgK
L
(D8/21) Forehead 2
E HG24MT High (Shikoku-Chugoku-Osaka; 15) HG24MT-D6 BgK
L
(EK) Forehead +
HG25SM Lower (Chubu-Tohoku; 15) HG25SM-D7 BgK
L
(EK) Forehead +
HG15HK Intermediate (Kyotod; 17) HG15HK-D10 BgK
L
(EK) Forehead +
HG16AT Tokyo (17) HG16AT-D22 BgK
L
(EK) Neck +
HG16AT-D25 BgK
L
(EK) Nape 2
G HG20SK Tokyo (16) HG20SK-D1 BgK
L
(G) Face +
I HG23TA High (Shikoku-Chugoku-Osaka; 18) HG23TA-D4 BgK
L
(I) Around the left eye 2
HG23TA-D5 BgK
L
(I) Left eye (conjunctivitis) 2
J HG29SD High (Shikoku-Chugoku-Osaka; 16) HG29SD-D12 Non-BgK
L
:non-BgO
L
(J) Ear 2
K HG30SS Low (Kyushu; 22) HG30SS-D13 BgK
L
(EK) Forehead 2
HG31IM Low (Kyushu; 16) HG31IM-D15 BgK
L
(EK) Forehead/head +
L HG32KK High (Shikoku-Chugoku-Osaka; 15) HG32KK-D16 BgK
L
(L16-20) Forehead +
HG33TM High (Shikoku-Chugoku-Osaka; 15) HG33TM-D17 Non-BgK
L
:non-BgO
L
(L17) Eye 2
HG34NM Lower (Kanto; 16) HG34NM-D18 BgK
L
(L16-20) Armpit 2
HG35HH Lower (Kanto; 18) HG35HH-D19 BgK
L
(L16-20) Chin +
HG36OK High (Shikoku-Chugoku-Osaka; 15) HG36OK-D20 BgK
L
(L16-20) Shoulder +
HG37IY Lower (Chubu-Tohoku; 19) HG37IY-D23 nonBgK
L
:nonBgO
L
(L23) Forehead 2
HG38OH Lower (Kanto; 23) HG38OH-D24 BgK
L
(L24) Neck 2
HG39OY Intermediate (Kyoto; 15) HG39OY-D26 BgK
L
(L26) Ear 2
*The geographical region where the sumo wrestler had lived before joining the stable and the wrestler’s age are given in parentheses.
DThe Kanto Region is located between the Chubu and Tohoku Regions and, therefore, within a lower BgK
L
RF (11 %) area (Ozawa et al., 2006).
dThe Kyoto Prefecture is located between the Shiga Prefecture, a low BgK
L
RF (27.3 %) area, and the Osaka Prefecture, a high BgK
L
RF (49.1 %) area (Ozawa et al., 2006). Therefore, the BgK
L
RF of
Kyoto is denoted as intermediate here.
HSV-1 RFLP variants associated with herpes gladiatorum
http://vir.sgmjournals.org 2413

all other stables, one HSV-1 strain was responsible for all HG
cases in that stable (Table 2 and data supplements B–G).
Eight different BgK
L
strains [BgK
L
(D3), BgK
L
(D8/21),
BgK
L
(EK), BgK
L
(G), BgK
L
(I), BgK
L
(L16–20), BgK
L
(L24)
and BgK
L
(L26)]were isolated from wrestlers in six stables,
one BgO
L
strain [BgO
L
(B)]was isolated from two wrestlers
in one stable and three different non-BgK
L
:non-BgO
L
strains [non-BgK
L
:non-BgO
L
(J), (L17) and (L23)]were
isolated from wrestlers in two stables (Table 2). These BgK
L
strains were all the BgK
L
:SaCFJ
M
:SaE
L
:SaGH
M
:KpM
S
variant except for BgK
L
(D3). The number of stables in
which BgK
L
was isolated (six) was larger than that in which
non-BgK
L
was isolated (three) (Table 2). Furthermore, for
sumo wrestlers with HG, the BgK
L
RF value of 81 % (17 of
the 21 BgK
L
-infected wrestlers with skin or eyelids lesions;
Table 2) was significantly higher (data supplement H) than
the BgK
L
RF of 27 % in the general population in Japan
(Ozawa et al., 2007).
In seven of the 22 (32 %) HG cases, eczematous lesions
with systemic illness were observed and these cases were
diagnosed as KVE (also called eczema herpeticum)
(Kramer et al., 2004; Marcus et al., 2005; Ruchman,
1954) (Table 2). All HSV-1 isolates from these KVE cases
were BgK
L
(Table 2).
Concurrent infections of different HSV-1 strains in HG
cases has been suggested previously (Belongia et al., 1991;
Dworkin et al., 1999) but the RFLP data were ambiguous.
The present study is, to our knowledge, the first to report
precise RFLP analyses, with many restriction endonucleases,
of HSV-1 isolates from HG cases. The living conditions of
professional sumo wrestlers suggested that the source of
primary HSV-1 infections among sumo wrestlers in each
stable was their fellow wrestlers. Three different BgK
L
strains
and two different non-BgK
L
:non-BgO
L
strains were isolated
from eight HG cases in stable L wrestlers. Five of these cases
were primary HSV-1 infections. These results indicate that
concurrent HSV-1 infections caused by different HSV-1
strains in wrestlers within the same sumo stable are common
(data supplement J).
In the field of sports medicine, recurrent HG has usually
been diagnosed simply based on symptoms and the
wrestler’s medical history (Anderson, 2005; Becker et al.,
1988; Strauss et al., 1989; Turbeville et al., 2006). Sumo
wrestlers’ HG cases were caused by non-primary HSV-1
infections as well as by primary HSV-1 infections. Repeated
HG recurrences within a short period of time and isolation
of HSV-1 isolates with different RFLP patterns from the
same sumo stable suggested reactivation of latent HSV-1
infections in these wrestlers. The frequent severe skin
damage of sumo wrestlers may impair subcutaneous nerve
cells and the strong physiological and mental stress
resulting from their hard practice regime may affect their
immunological status (data supplement I). This may
explain why HG recurred in a number of sumo wresters.
The possibility of an immunological effect is supported by
the results reported here, since wrestlers who did not
develop HG had high titres of neutralizing antibodies
compared with pre-HG sera from wrestlers who were
susceptible to recurrent HG.
The high association of BgK
L
with sumo wrestlers’ KVE is
statistically significant (P50.03, Fisher’s exact test).
Therefore, a BgK
L
-related mutation(s) may enhance
HSV-1 pathogenicity in skin or affect the host immuno-
logical response.
Finally, the BgK
L
RF in professional sumo wrestler HG cases
was higher than that in the general population in Japan; this
difference was statistically significant. In addition, the
number of different BgK
L
strains isolated from sumo
wrestler HG cases was larger than the number of BgO
L
and non-BgK
L
:non-BgO
L
variants isolated from these cases;
the number of stables in which BgK
L
was isolated was also
larger than that in which non-BgK
L
was isolated.
Taken together, these results suggest that latent BgK
L
infections were reactivated and transmitted more efficiently
than latent non-BgK
L
infections in these cases (data
supplement K). Future studies in this laboratory will
analyse the genome sequences of these BgK
L
clinical
isolates. As far as we are aware, the present study is the
first to suggest that the efficiency of HSV-1 reactivation/
recurrence in humans may depend on the HSV-1 variant
or strain and it supports the BgK
L
dispersion hypothesis
(Eda et al., 2007; Ozawa et al., 2006, 2007).
Acknowledgements
We thank Drs S. Okabe, E. Ichikawa and E. Okubo and Doai Kinen
Hospital for contributions to an initial stage of this study and Mr R.
Kitamura for technical assistance.
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HSV-1 RFLP variants associated with herpes gladiatorum
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