Jpn. J. Infect. Dis., 54, 47‑54, 2001

Review

Human Herpesviruses 6 and 7: Effects on HematopoleSis

and Mode of Transmission
Masao Yamada*
Department of ny10logy, Okayama Universiy Graduate School ofMedicine and Dentistry,
Shikata 2‑5‑1, Okayama 700‑8558, Japan(Received February 5, 2001. Accepted March 22, 2001)
CONTENTS:
Summarylntroduction

General characteristics of HHV‑6 and HHV‑7
HHV‑6: as a causative agent of myelosuppression after stem cell transplantation
l. Monitorlng Of herpesviruses a触r allogeneic peripheral blood stem cell transplantation
and bone ma汀OW transplantation

2. Suppressive effects ofHHV‑6 0n in vitro hematopoletic colony formation
Mode of transmission or HHV‑6 and HHV‑7
1. Molecular epidemiology ofHHV‑7
2. Kinetics of the vims production in saliva of healthy adults
3. Seroepidemiology of HHV‑6 and HHV‑7 based on neutralizing assay
Conclusion

SUMMARY: Human herpesvirus 6 (HHVl6) and human herpesviruS 7 (HHV‑7) were recently disc.overed, andare known as etiologic agents of exanthem subitum (roseola). HHV‑6 and HHV‑7 are TJlymphotroplC, and havebeen classified as betaherpesviruses. In monitorlng Of herpesviruses a洗er hematopoletic stem cell transplanta‑tion, each herpesvirus had a unlque temporal profile of detection. HHV16 DNA was detected mostfrequently at
3 weeks, whereas cytom?galovirus and Epstein‑Barr virus DNA were detected lよter･ HHVl7 DNA was not detected

throughout the obseⅣatlOn period. ln in vitro hematopoletic colony assays, HHV‑6 suppressed all three lin°ages

of hematopoleSis, i.e., erythroid, granulocyte/macrophage, and megakaryocyte, whereas HHV‑7 did not haveany suppressive e飴ct. Molecular epidemiologlCal analysts revealed that HHV‑7 was transmitted horizontally
丘Om grandparents to parents to chil血en through close contact within a household･ Either parent could transmit

HHV‑7 to the children. Follow‑up studies of the amount ofviral DNA in saliva samples revealed that the amountof HHV‑7 DNA was rather constant f♭r each individual, and that "high producers" and ‖low producersM could be

distinguished. Transferred antibodies agalnSt HHV‑7 tended to be higher and remain longer alter birth than thoseof HHV‑6, and these findings are consistent with the clinical observation that HHVl6 infection occurs earlier
than HHV17 infection.

transmission are introduced.

Introd uction

General characteristics of HHV‑6 and HHV‑7
The virions ofHHV‑6 and HHV‑7 consist of four ultra‑

Human herpesvirus 6 (HHV‑6) †as first isolated fromperipheral blood lymphocytes of patlentS With lymphopr0‑
1iferative disorders in 1986 (1), and has been divided into

structural components that are common to all herpesviruses;

two variants, HHVl6A and HHV‑6B (2,3). Yamanishi et al.(4)a centrally‑located core containlng the viral genome,

clearly demonstrated an etiologlCal relationship between

surrounded by three concentric structures‑the capsid, theprimary HHV‑6 infection and exanthem subitum. Human
herpesvirus 7 (HHV‑7) was first isolated from the peripheral
blood lymphocytes (5) and saliva ofhealthy adults (6). HHV‑
6 and HHV‑7 are predomipantly T‑lymphotropic (7‑10),

tegument, and the envelope that is studdedwith virus‑encoded
glycoproteins. The virions ofHHV‑6 and HHV‑7 are 170‑
200 nm in diameter and have a distinct layer ortegument

exhibit considerable genomlC Sequence homology, and are(14,15) (Fig. 1). Maturation of these viruses appears to beprocessed by a pathway that includes 1) capsid formation inclassified as members of the Roseolovirus genus of thethe nucleus, 2) envelopment of the capsid at inner nuclear

Betaherpesvirinae sub family (1 1‑1 3). ln this short review,

membranes, 3) de‑envelopment into the cytoplasm, 4) re‑

the general characteristics of these two viruses are compara‑eγelopment of the resulting cytoplasmic capsid at a cytoplas一

tively discussed, then two toplCS related to our recent studies

mlC membrane (budding into vacuoles), 5) transport to theon pathogeniclty in the hematopoletic system and mode ofplasma membrane, and 6) release by reverse phagocytosis(14,15).
*Corresponding author: Tel: +81 ‑86123517 I 63, Fax: +8 I ‑86‑235‑

The HHV‑6 genome is approximately 160 kbp in length,
and includes approximately 100 genes (16‑ 18). The HHV‑7

7 1 69, E‑mail: masao@md.okayama‑u.acjp
47

caused by prlmary infections of either HHVl6 or HHV‑7 inchildhood usually resolve spontaneously, several cases ofcomplications have been reported (23‑26). HHV･6 and HHV‑
7 are thought to establish latent, life‑long infection like othermembers of the herpesviruses. It has been reported that HHV‑
6 may contribute to life‑threatenlng diseases in immunosup‑

pressed conditions such as organ transplant and AIDS (27‑30)･ A variety of diseases, such as chronic fatigue syndrome,
histiocytlC neCrOtizlng lymphadenitis, mononucleosis‑like
syndrome, and multiple sclerosis have been reported to be

associated with HHV‑6 (31‑35). No reliable link between
reactivation of HHV‑7 and a disease has been demonstrated
thus far (36,37).

HHV‑6: as a causative agent ofmyelosuppression

Fig. 1. HHV‑7 virions on the surface of an infected cord blood mon0‑

after stem cell transplantation

muclear cell. Bar: 100 nm.

l･ Momitoring of herpesviruses after allogeneic periph‑eral blood stem cell transplantation and bone marrowgenome, with a length of approximately 145 kbp, lS morecompact than the HHV‑6 genome (19)･ About 40 g?nes oftransplantation

HHV‑6 and HHV17 encode structural proteins or protelnS that

Recently, more attention has been fbcused on the activlty

are involved in the lytlC‑Cycles of genome replication, andof herpesvimses after bone marrow transplantation and otherare homologs of genes that are shared by all members orthe

types of hematopoietic stem cell transplantation (38‑40).

family Herpesviridae. These are referred to as "herpesvirus

CMV, HHV‑6, and Epstein‑Barr virus (EBV) Were associ‑core genes"･ Three members of the Betaherpesvirinae sub‑ated with failure of marrow engraftment and other types offamily, cytomegalovirus (CMV), HHV‑6, and HHV‑7, arecomplications such as pneumonitis, encephalitis, and poshsimilar in the arrangement of the herpesvirus core genes,

transplantation lymphoproliferative disorder (PTLD).

which are located in the central part of the genomes. A handful

We recently monitored the activityof four herpesviru.sesof genes are specific to the Roseolovirus genus･ Nearly every

after allogeneic peripheral blood stem cell transplantatlOn

HHV17 gene has a counterpart in HHV‑6. However, one gene(allo‑PBSCT) and bone marrow transplantation (allo‑BMT)(the U94 gene), a homolog of the parvovirus rep gene,.is(41). Ⅵral genomes in peripheral blood leukocytes of thepresent in both HHV‑6A and HHV‑6B but is not present ln
HHV‑7 (20,21).
Clinically, HHV‑6Ii and HHV‑7 are the common etiologlC

patients were detected by PCR. Each herpesvirus had aunlquetemporal pro丘le ordetection. HHV‑6 DNA was detected mostfrequently at 3 weeks after transplantation, whereas CMV

agents or exanthem subitum (roseola), whereas diseases

and EBV DNAs were detected later, at 2‑3 months a洗er trans‑caused by HHV‑6A are less apparent (4, 22). While diseaseslヒplantation (Fig. 2). Detection rates ofHHV‑6 DNA at 3 and 4

B v 80 60 40 20a^!)!sod%

P

2W

3W

4W

2m

3m

6m

P

H H V l6

2W

3W

4W

2m

3m

6m

HHV‑7
80

8 60 0a^!)!sod%‑■･･･ PBSCT

60

r▲‑

BMT

40

4 20 0

20
0

P

2W

3W

4W

2m

3m

P

6m

2W

3W

4W

2m

3m

6m

Fig･ 2･ Detection rates ofEBV, CMV, HHV‑6, and HHV‑7 DNA in peripheral blood leukocytes of patients afteral10‑PBSCT(closed squares) and alto‑BMT (closed triangles). Blood samples were coHected 1 ‑2 weeks before transplantation (p) and 2,
3, and 4 weeks (2W, 3W, and 4W), and 2, 3, and 6 months (2m, 3m, and 6m) after transplantation.

48(ref. 41)a) PBSCT

2. Suppressive effects of HHV‑6 0n in vitro hemato‑
poietic colony formation
These clinical observations urgedusto evaluate the inhibi‑o 'oN∧lO一at 21dIo^!lニ!qe OJd

tory effects of HHV‑6 and a related betaherpesviruS, HHV‑7,
806

0n hematopoietic progenitors in vitro. We employed colony0

assays in a semisolid matrix supplemented with various

hematopoletic cytokines. Using T‑cell depleted cord blood
m?nPnuclear cells as a source (42)･ We established hematoI

poletlC COlony ass.ays for three lineages, including 1) CFU‑
GM (colony‑ formlng unit granulocyte/macrophage) colonies
for !ranulocyte/macrophage lineage, 2) BFU‑E (burst‑
formlng unit erythroid) colonies for erythroid lineage, and

3) CFU‑Meg (colony‑foming unit megakaryocyte) Colonies

0
0

20

40

60

for megakaryocyte lineage. CFU‑GM and BFU‑E colonleS80

can be assayed togetherinthe presence ofa cocktail of cytokines,

Days after transplantation

stem cell factor (SCF), GM‑CSF, IL‑3, and erythropoietin,
whereas CFU‑Meg colonies requlre a Special cytokine,b) BMTo JoN∧1〇一Olt2Id o^!)ニ!qt2qOJd

thrombopoietin (TPO).

100

Effects ofHHV‑6 and HHV‑7 on CFU‑GM and BFU‑E were
examined first (43). T‑cell depleted cord blood mononuclear

80

cells were infected with one of these viruses and subjected tothe hematopoletic colony assay ln a Semisolid matrix. Ten to60

12 days after plating, CFUIGM and BFU‑E colonies werecounted. HHV‑6B, a more prevalent variant of HHV‑6,40

suppressed bothCFUIGMand BFU‑E coloniesina multiplicity
of infection (MOI)‑dependent manner, and the other less20

prevalent variant, HHV16A, also had a suppressive effect.
However, HHVl7 did not have any suppressive effect on BFU‑

0

E or CFUIGM. Compared with the mock‑infected culture,
0

20

40

60

80

the size of both types of colonies were also reduced in HHV‑
Days aAer transplantation

6 infected culture. When slngle colonies of each type were
picked up from the infected culture and separately examined,

Fig. 3. Time course of platelet engraftment after a) allo‑PBSCT andb)

alto‑BMT(ref.

HHV‑6 was detected by PCR in most of the colonies ofCFU‑

41)

GM and BFU‑E.
Compared to erythroid and granulocyte/macrophagecolonies, megakaryocyte colonies had been very difficult

weeks aRer alloIBMT were slgnificantly higher than thoseafter allo‑PBSCT. However, the detection rates of the otherthree herpesviruses were not slgnificantly different between
allo‑BMT and allo‑PB SCT throughout the observation period.

to establish until the recent discovery of the genuine mega‑

Furthermore, delayed platelet engraftment was a.ssociatedestablish culture conditions for rpegakaryocyte colonies (46)･

with detection ofHHV‑6 DNA at the first 4 weeks after allo‑
PBSCT. Figure 3 shows the kinetics of platelet engraftment

Two types ofTPO‑induced colonleS, CFU‑Meg and non‑CFUI

of patients who were positive for HHV‑6 at the first 4 Weeks

colonies was based on their characteristic morphology, 1.e.,and of those who were negative for HHV‑6 after allo‑PBSCTtranslucent cytoplasm and a highly refractile cell membrane,or alloIBMT. Platelet engraftment after allo‑PBSCT was

and was confirmed by immunohistochemistry to detect theslgnificantly slower in HHV‑6 positive patients than in HHV‑

CD4 1 antlgen. Optimization of culture conditions fわr TPO‑

6 negative patients.

inducible colonies was attempted in the presence or absence

karyocyte colony stimulation factor, TPO (44,45). We took
advantage of the availability of recombinant human TPO to

Meg colonies, were generated. Identification of CFU‑Megof fetal calf serumand SCF.

The amounts of HHV｣6 DNA detected within 4 Weeks a洗er

transplantation were also compared between patients with

Effects of two variants of HHV‑6 and HHV‑7 on TPO‑

delayed and those with normal platelet engraRment. Patients

inducible colonies were examined under semm‑containlng

with delayed platelet engraftment exhibited a greater amountconditions. T cell‑depleted cord blood mononuclear cells wereof HHV‑6 DNA than did patients with nomal engraftment.

infected with either HHV‑6 or HHV‑7, and were subjected to
TP0‑inducible colony assay. As shown in Fig. 4, HHV‑6B

None of the other herpesviruses were associated with the delayof platelet engrallment in tens of detection rates or amount

inhibited CFU‑Meg colony fわrmation in a MOLdependenttion aRer allo‑PBSCT as compared with alloIBMT; i.e., rapidmanner and HHV‑6A had a similar inhibitory effect. On thecontrary, HHV17 had no effect. To confirmthe suppressive
effect of HHV‑6 on CFU‑Meg, experiments were repeatedrecovery of CD4+ T cells after allo‑PBSCT might be more

under several conditions. Under serum‑free conditions, either

ofviral DNA in the first 4 weeks alter transplantation. These
results suggest an advantage in immunologlCal reconstmc‑

prominent in the early stage, when HHV‑6 is most likely toin the absence or presence or SCF, HHV‑6 suppressed CFU‑

reactivate. Thus, allo‑PBSCT is more beneficial than allot

Meg colony fわrmation in a MOI‑dependent manner. Heat

BMT in te‑S of prevention orcomplications caused by HHV‑

inactivation and ultra‑filtration of the virus sample completely

abolished the suppressive effect of HHV‑6, suggestlng that

6 reactivation.

the suppression was due to the presence of the infectiousviruS.
Combined wi血the results on the eⅣthroid and granulocyte/49and HHV‑7 infections are very high throughout the world
and that almost all people are exposed first to HHVl6 andsecond to HHV‑7 in their childhood (22,48). By adulthood,

MockHHV‑6B(Z29)HHV‑7HHV‑6A lMRK)tUllO2)

6av ･⊃jU 6evq･⊃jUuOu

most individuals are seroimmune even if no specific febrile

80 60 40 20 0 20 40

Sa!UOl0310Laq∈nN

illness was ever recognized. Thus, like most human herpes‑
ii ;…Z:≡::;

viruses, HHV‑6 and HHV‑7 are ubiqultOuS in the human popula‑tion and likely to persistina latent state a洗er prlmary infection.

Several investlgatOrS have reported that HHV‑7 is easily
isolated from the saliva of individuals who had antibodies toi

HHV‑7 (6,49,50). Because the vims is an inhabitant in saliva
of a maJorlty Of healthy adults, horizontal transmission fromparent to child is highly likely, but this mode of transmissionofHHV‑7 has yet to be firmly documented. Therefore, we
conducted a series of studies to obtain evidence ofintrafamilial
MOI

1

MO‖

0

MOH

MOI

1

transmission ofHHV‑7 (5 1).

Fig. 4. Effects ofHHV‑6 and HHV‑7 on TPO‑induciblc colonies. Number

We set out to isolate HHV‑7 from the saliva samples of all

ofCFU‑Meg colonies (lIIIcd barヲ･ colonies consisting of 50 0r moremembers of six families, including four families with threecclls; open bars, colonies consistlng Offewcr than 50 cells) and non‑generations living in the same household. As a result, HHV‑CFU‑Meg colonies (shaded bars) after infection with HHV‑6 and
HHV‑7.

(ref.

7 was isolated from saliva samples of43 of47 participants

46)(91.5%). Every isolate was subjected to DNA restriction
analysis. The results are summarized in Fig. 6. In family #1,
macrophage colonies, HHV‑6 suppressed all three lin°ages

the restriction pattems of the mother and three of the fわurofhematopoietic colony fbmation in vitro (Fig. 5). Thus, We

chil血en were similar, and the pattems of the patemal grand‑

focused on an earlier stage of hematopoleSis, i.e., a lineage‑mother and the father were similar. In family #2, the pattems

uncommitted progenitor step, and examined the interactionof the matemal grandmother, the mother, and three children

between HHV‑6 and CD34+ cells, which are generally thought
to be the major s?urce of hematopoietic progenitor cells (47)･

were similar, and the pattems of the paternal grandmotherand the father were similar. ln family #3, the pattems of the

In order to examlne Whether CD34+ cells are susceptible to
HHV‑6, we purified CD34+ cells with magnetic beads andinfected them with HHVl6. Three days after infection, we

patterns of the paternal grandfather and the father wererelated; the pattem of the child did not match the pattem ofreselected CD34+ cells and obtained more than 99% purlty.

any other family member. ln family #4, which included three

The HHV‑6 genome was detected in the highly‑purified
CD34+ cells by in situ hybridization.

generations, two palrS Of related patterns were observed

matemal grandmother and the mother were similar, and theamong siblings, but neither or these pattems matched any of
those of the senior members of the family. ln family #5, thepattem of the father as well as those offive of six children

Mode of transmission of HHV‑6 and HHVl7

were similar, and those of the mother and the other child were

1. Molecular epidemiology or HHV7

similar. ln family #6, the father and a child had related

SerologlC Studies showed that the prevalences of HHV‑6

pattems, and the patterns of the mother and another childlineage‑

Lineage‑committed

uncommittedprogenitors

Effects of HHV‑6
Erythroid

progenitors

lineagelnhibitory

Multipotent
stem cell

Granulocyte/

CFU‑GEMM CFU‑GM

macrophage lineage

rnhibitory

CD34+ cells
Megakaryocyte
lineagelnhibitory

Figl 5･ Hematopoletic diffcrcntiation and the supprcssivc cfrects of HHV‑6 0n thrcc lincagcs. Rcsponsiblc hematopoletic

cytokincs for each lincagc are underlined. Epo, erythropoletin; GM‑CSF, granulocyte/macrophagc‑colony stimulation
factor; SCF, stem cell factor: TPO, thrombopoletin.

50

Family #lFamily #2of breast feeding was also obtained from each mother in the

study. But there was no apparent correlation between breast

feeding and matemal transmission within a family; e.g., infamily #3 with a history of breast feeding, HHV‑7 transmis‑

三≡ 三‑=二三三
15

13

11

6

6

4

sion occurred from a father to his children. The results clearly

showed that HHV‑7 was transmitted horizontally fromgeneration to generation in families living in the same house‑2

hold. The data also showed that fathers as well as mothers
Family #3

Family #4

transmitted the infection.

2･ Kinetics of the virus production in saliva of healthy
adults

HHV‑7, as well as HHV‑6, is thought to be transmitted
during early infancy through saliva. However, the kinetics ofvirus shedding ln Sahva of healthy adults, kom whom children
33

31

29

28

are assumed to acqulre the viruses, is mostly unknown. HHV‑

26

7 is more readily lSOlated from saliva ofhealthy adults thanis HHV･6･ The next question we posed was how many copleS

Family #6of the HHV‑6 and HHV‑7 genomes were secreted in the salivaof healthy adults.

The number of copleS OfHHV‑6 and HHV‑7 genomes insaliva samples was determined by the quantitative PCR
20

18

13

11

9

4

11

procedure (52). The genomes ofHHV‑6 and HHV‑7 were10

respectively detected in 41.3 % and 89.7 % of the saliva

Fig. 6. Pedigrees of six families examined by restriction analysis of
HHV‑7 DNA. Male and female are indicated as boxes and circles,

samples from 29 healthy adults. The average DNA copy

rcspectively. Persons from whom HHV‑7 was isolated are shaded. A

number of the HHV‑6 genome in the positive samples (4.8 ×

p.erson who was already decreased is marked (i)･ Members having

103 copies/ml) was much lower than that of the HHV‑7

slmiIar HHV17 DNA restriction pattems are connectedwithbold lines.
Numbers under the boxes and circles indicate ages.

genome (1.4 × 104 copies/ml). Only 4 out of29 individuals(ref. 5 1)

exhibited more HHV‑6 DNA than HHV‑7 DNA.
The vims DNA load of sequential samples丘om six healthy

were related.

adults was monitored for 3 months, and the relationship

The similarities in restriction profiles of family members

between the number of copleS Orthe two genomes is shown

were summarized. ln total, similar pattems with the motherin Fig. 7. The am(山nt ofHHV‑7 DNA was ra也er constant f♭rwere found in 48% ofoffsprlng Ofthe families, and similar

each individual. Some individuals (d and q were "high‑pattems with the father were found in 28% of offspring. History

producers'', and others (b and e) were ‖low producers" of(t∈＼sa!do3)L･>H 1 05 1 04 が.1e

T‑1｣l
l1

(t∈＼sa!doD)L･AH

1 1 01 0 0

7‑i

5 4 3

NDIO2

103

104

105

HHV‑6 (copies/ml)

NDIO2

103

104

105

HHV‑6 (copies/ml)

ND

103

104

105

HHV‑6 (copies/ml)

Fig･ 7･ Number of copies of the HHV‑7 gcnome plotted in relation to the number of copies ofHHV‑6 (logarithmic scales) in
saliva samples of six individuals (a‑i) during 3 months offollow‑up period. For each subject, the first point is shownwith
a large circle and the poJnts arcthen connected in chronologlCalorder.

51(ref. 52)(uN)｣3一!一t 0!一t!2!t !1ln3N

ro
8

6

4

2

0

享｢1享｢汗
0.5

1.0

1.5

2.0

Co. ro.
Age (y.0.)

Fig. 8. Changes ofncutralizing antibody tltCrS agalnSt HHV‑6 and HHV‑7 in five infants,

HHV‑7 DNA. ln contrast, the amount ofHHV6 DNA varied

ConcLusion

drastically over time in each individual,from below detection
limit to more than I.0 X 105 copies/ml. In subjects a and c,

While diseases caused by HHV‑6 and HHV‑7 in children

the amounts of both HHV‑6 and HHV｣7 DNA were extremely

usually resolve spontaneously, life‑threatenlng Cases related

variable.

to HHV‑6 in childhood and immunocompromised hosts in

We also examined the relationship between the copy number

cases of stem cell and solid organ transplantation have beenof the genome and the presence of infectious viruses. Although
HHV‑6 was never isolated from the saliva, HHV‑7 wasreported. These conditions warrant the development ofeffective antiviral agents against HHV‑6 (54‑56)･

isolated from the saliva several times during the follow‑up

period. The amount orHHV｣7 DNA tended to be higher at

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G., Biberfeld, P., Wong‑Staal, F., Kramarsky, B. andthe virus was not isolated. However, failure to isolate HHV‑6from the saliva samples cannot be attributed to the scarclty

of the amounts ofHHV｣6 DNA, because at several time polntS
the amounts orHHV｣6 DNA were almost comparable to the

Gallo, 良. C. (1986): Isolation ofa new vims, HBIJV in

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Z･ and Gallo, R･ C･ (1991)‥ Genomic. polyrporphism,

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ferred antibody titers agalnSt HHV‑7 Were higher and tended

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these findings are in accord with the clinical observation that

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7 is a constitutive inhabitant of adult human saliva. ∫.

52

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A., Bememan, Z. N. and Gallo, 良. C. (1994): CD4 is a

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