Jpn. J. Infect. Dis., 53, 137‑155, 2000

Review

Human Herpesvims 8‑Virology, Epidemiology and Related Diseases A
Harutaka Katano* and Tetsutaro Sata

Department ofPathology, National Institute of Infectious Diseases,

Toyama 1‑23‑1, Shinjuku‑ku, Too/0 162‑8640, Japan(Received June 22, 2000. Accepted July 3 1, 2000)

CONTENTS :Summ ary

I. Introduction

2. Virology

3. Diagnosis ofHHV‑8 infection
3.1 PCR
3.2 Histological detection of HHV‑8

2. 1 Classification

2.2 Virion morphology

3.3 Serology

4. Epidemiology
4. 1 Seroprevalence and transmission

2.3 Genome stmc山re and gene expression

4.2 Molecular epidemiology

2.3. 1 Immediate‑early genes

2.3.2 Early genes

2.3.3 Late genes
2.3.4 Latent genes

5. HHV‑8 related diseases
5.1 Kaposi's sarcoma
5.2 Primary effusion lymphoma

2.4 HHV‑8‑encoded cytokines and

5.3

2.4.1 Viral cytokines
2.4.2 Viral oncoproteins

Multicentric Castleman's disease

5.4 AIDS‑associated anaplastic large cell lymphoma

oncoproteins

5.5

0thers

6. Conclusion

2.5 Experimental infection in vitro

SUMMARY: Human herpesviruS 8 (lHHVl8], Kaposi's sarcoma‑associated herpesvirus lKSHV]) is a.novel
human oncovirus classified as a gamma‑herpesviruS. HHV‑8 is associatedwith Kaposi's sarcoma (KS), prlmary
effusion lymphoma (PEL) and some cases ofmulticentriC Castleman's disease (MCD). Antibodies against HHVl
8 are detectedinthe sera of almost all KS patients, about 30% ofHIV‑infected homosexual males in the world
and 1.4% of the Japanese population. In HHVl8‑associated mahgnancies such as KS and PEL, HHV‑8 1atently
infects these tumor cells. Unhke other viruses, HHV18 encodes several human homologues including cytokines(Ⅰし6, MIPs, IRFs) and regulatory proteins (cyclin D, G‑protein coupled receptor [GPCR])･ These prote享ns may

play slgnificant roles in the pathogenesis of HHV‑8‑associated diseases. lt has been demonstrated in vltrO thatthe functions of retinoblastoma and p53 proteins were inhibited by viral cyclin D and latency‑associated nuclear

antlgen, respectively. Mice transgenic for GPCR have a KS‑like reg10n in the skin･ These data suggest the fulloncogenecity of HHV‑8･ On the other hand, many cells expresslng lytic proteins are fわund in MCD tissues,suggesting that the pathogenesis of MCD is different from that of HHV‑8‑associated malignancies･

analysis (2)･ andthe virus was designated as Kaposi's sarFoma‑

1. Introduction

associated herpesvirus (KSHV) or human herpesvlruS 8

In 1994, Chang et al. reported that two novel DNA frag‑ments were discovered in Kaposi's sarcoma (KS) tissues (1).
They used representational difference analysis (RDA), which(HHV‑8). The isolation ofa new virus from KS tissues had ais one of the subtraction PCR‑based methods of purifying

slgmificant finding that could explain the pathogenesis ofmalignant tumors. Since dematologists had suspected an
infectiousviral ongln Of KS based on its clinical charac‑
teristics, they expected the effective management of KS uslng
antiviral drugs. Molecular biologlStS Who use gene subtrac‑
tion methods considered RDA as a revolutionary method.

great impact on many scientists of various fields. Pathologists

considered the association of virus infection with KS to be a

restriction‑endonuclease‑digested fragments present in one

population of DNA fragments but not in others. SurglCaIIy
removed specimens of KS and normal skinWere investigatedby means of the RDA, and the 330‑ and 631‑nucleotide
fragments were detected to be specific for KS (1). Since thesesequences of the DNAfragments were found to be homologous

VirologlStS considered the discovery of a novel human herpesIwith herpesvirus saimiri(HVS) and Epstein‑Barr virus (EBV),

virus very ipportant･ Because both HVS and EBV are thought

they were considered as fragments of a novel human herpes‑

也 be oncovlmSeS CauSlng lymphomas in monkeys and humans,

virus. Two years later, he叩eSVirus‑like particles orthis vims

HHV‑8 was presumed to be a new oncoviruS･ It has beenshown that some HHV‑8 encoded genes are homologouswith

were fわund in lymphoma cells by electron､microscoplCal

oncogenes or cell cycle‑associated genes. In this review, we*Corresponding author: Tel: +81‑3‑5285‑ll 1 1 ext. 2627, Fax:summarize thevirologlCal and epidemiologlCal aspects of
HHV‑8 infections, and HHV‑8‑associated diseases.

+8ト3‑5285‑I I 89, E‑mail: katano@nih.go.jp

137

仇at of CMV by electron microscopy; that is the tegument of

2. Virology

CMV has a higher density than that ofHHV‑8, and CMV is

2.1 Classification
HHV‑8 is a new gamma herpesvirus classified as a member

accompanied by numerous dense bodies su汀Ounding viralparticles in the cytoplasm of infected cells which are notpresent in HHV‑8‑infected cells (6).

of Rhadinovirus (gammal2 herpesviruS)･ In号eneral, herpes‑

viruses are classified into three sub families, I.e., alpha, beta
and gamma. Herpes simplex virusl 1 , ‑2 and varicella‑zoster
virus (VZV) belong to the alpha sub family, cytomegaloviruS(CMV), HHV‑6 and ‑7 to the beta subfamily, and EBV and

2.3 Genome structure and gene expression
The HHV‑8 genome consists ofa linear and double‑stranded
DNA about 170 kbp in length (9), which was sequenced

HHV‑8 to the gamma subfamily. The gamma herpesviruses

almost completely wi仇in two years a鮎r its disc?very (10)･

are further classified into lymphocryptoviruses (gamfna‑ 1

The HHV‑8 genome consists of a long空que reglOn (LUR)

herpesvirus) and rhadinoviruses (gamma‑2 he叩eSVlmS).

and a teminal repeat (TR) at both te‑lnl, Which resembles
the HVS structure (10) (Fig. 2). TR consists of an 801‑bp
direct repeat unit with 84.5% GC content. The number or
repeatsinTR may vary･ The LUR is 140･5 kbp and has 53･5%
GC content.

While EBV is the prototype of lymphocryptovimses, HHV‑8
is a rhadinovirus, as. are HVS, h叩eSVims ateles (HVA)
and rhesus rhadinovlruS (RRV) (3)･ Seq†encing analysis

has revealed that HHV‑8 is genetically slmilar to HVS･ A
recent study categorized rhadinoviruses into two, i･e･, New‑and Old‑World gamma‑2 he叩eSViruses (4)･ Although

HHV‑8 encodes more than 80 viral proteins on LUR (Fig.
2). The open reading frames (ORFs) are divided into twolymphocryptoviruses have been found only in Old World

groups･ The first group has a sequence homology to HVS

primates, rhadinoviruses have been found in both New‑(HVAand is designated as ORF‑(number)･ The second group has.no

and HVS) and Old‑(HHV‑8 and RRV) World primates. Thus

homology to HVS and is designated as K‑(number)･ KinetlCS

far, there is no report that HHV‑8 was detectedinmonkeys,
however, these genetic data suggest that HHV‑8 may haveoriginated from African monkeys (4).

of HHV‑8‑encoded genes was mainly investigated in HHV‑
8‑infected primary effusion lymphoma cell lines stimulatedwith a phorbol ester such as 1 2‑0‑tetradecanoylphorbo1‑ 13‑
acetate (TPA) (1 1 )･ Like, other herpesviruses, the viral g?nes

2.2 Virion morphology
A complete viral particle orHHV‑8 is 150 ‑ 200 nm inwere categorized into lytic and latent genes and also Into

diameter and consists ora capsid and an envelope (2, 5‑8)expressions. The putative functions of HHV‑8‑encoded proteins

similar to those of other human herpesviruses (Fig. 1A andare summarized in Table 1.

immediate‑early (IE), early and late genes based on their

2.3.1 Immediate‑early (IE) genes
Zhu et al. identified four cDNAs from HHV‑8‑infected cellslB). In仇e nucleus, vims particles have a nucleocapsid (100nm in diameter) without an envelope. The viral capsid

contains a central DNA core, which appears to have a highelectron density. The envelope is derivedfromthe inner nuclear

by inducing viral reactivation in the presence of cyclohex‑

imide (CHX) and designated them as KIE‑1 (encoding
ORF50, K8 and K8.2), KIE‑2 (encoding ORF45), KIE‑3

membrane, when viral particles bud into the cytoplasm fromthe nucleus. The tegument protein fills the space between the(encoding K4.2, K4. 1 and K4) and KIEl4 (unknown) (12).
Among these, two IE proteins were extensively investlgated･
The first identified IE gene is ORF50 that is a homologue

nucleocapsid and envelope. It is generally accepted that仇e

features of viral particles are qulte Similar among herpes‑

somehow depend on the type or vims. In comparison wi仙of Rta, a transcriptional activator e.ncoded by EBV (1 1 ‑ 14)･
TranscrlptlOn Of ORF50 results ln its expression within

other herpesviruses, the viral particle canbe distinguished &om

4 h a洗er stimulation by TPA. This expression could not beviruses, but related structures formlng in the infected cells

二二iFig･ 1 ･ ElectronmicroPeopy of HHVl8･ Viral particles (virus capsids) in the nucleus (A) and cell surface (B) in the TPA‑

induced HHV‑8‑posltlVe Cell line TYll. Bar = loo nm. (Photograph by Ms･ E･ Moriishi)

138

K2

KI O4

06

07

08

09

10 11

19

K4

02

KS

K4.1
K3 70

K6

K4.2

26

20

K7
16 17 18

27

21

22

23

24

25

21

T1.1
5

30

10

15

34

31

33

35

29b

32

29a

50

36

41

37

3940

47

4243

60

65

66
63

105

44

45

65

110

115

52

48

SO K8

69

40

45

50

53

5556

80

57

K9

72

125

KIO VIRF‑3Kll S85960

85

K14

K12

120

VIR F‑2

54

75

71
67

35

KB.1

49

70

68

64

30

25

46

38

55

62

100

20

90

95

61

1

00

LAMP
73

130

74

135

75

KIS

140

TR

145

150

Fig. 2. Genomic map of HHV18. 0RFs are indicated by arrows. Gray arrows indicate that functions ofORF were reported(Refer to Table I ). TR=terminalrepeat, vIRF=viral interferon regulatory factor, LAMP=latency‑associated membrane protein.

region (1 1,16,17). The amino acid sequence ofK8 protein

blocked by phosphonoacetic acid (lnもA1 , a herpesviruS‑DNA

polymerase inhibitor) nor CHX (a protein synthesis inhibitor).

shows a slgnificant homology to that of BZLF 1 , which plays aTransfection of ORF50 to HHV‑8‑infected cells resulted in

key role in仇e replication and reactivation orEBV However,

the activation of lytic gene expression ( I 3). TYle tranSaCtivation

the functional data of K8 as a transcrlPtlOnal activator have

was blocked by deletion of the C‑terminal of ORF50. Inter‑not yet been reported.

estlngly, it was demonstrated that the C‑terminal deletion

The K8. I protein was cloned as an immunogenic glyco‑

mutant of ORF50functioned as a dominant negative protein

protein (gp35‑37) using patients'sera or the monoclonal(13). Thus, ORf50 protein plays an essential role in the reacti‑
vation oflatent HHV‑8 in B cells. Another IE gene is K5 (15)whose expression is also unaffected by PAA and CHX,

generate two spliced variants, K8. 1A and K8.1B (19). These
proteinswere effectively reacted with humanserafrom HHV‑81

antibody against HHV‑8 (18,19). ORF‑K8.1 was fわund to

confirmlng its IE nature. The association of these two IE

infected individuals by Westem blotting; thus, K8. 1 may be aproteins is not the same as仇at ofIEl and IE2 ofCMV (15).

useful antigen for serological assays ( 1 8‑2 1 ). ImmunoelectronTransient‑transfection assays showed that the K5 promoter
was transactivated by ORF50 (1 5). In addition, the K5 protein

microscopy revealed that the K8. 1 protein is localized on both

is localized in the cytoplasm of induced and transfected cells

associated glycoprotein (20).

(15). Thus, it is difficult to consider the functions ofK5 Solely

Nucleic acid replication proteins of.HHV‑8 are expressedin the early or late phase. ORF59 (PF‑8) is a processivity
factor of viral DNA polymerase encoded by ORF9 (22).

cell and virion surfaces, suggestlng that K8.1 is a virion‑

from its localization and kinetics. Further studies are needed

to clarify the function ofK5.
2.3.2 Early genes

ORF54 is also an early protein hydrolyzlng dUTP to dUMP

In herpesviruses, early genes are defined as genes whose(23).

expression is blocked by CHX but not by PAA. In gene
expression studies, early genes encoded by HIIV‑8 were

2.3.3 Late genes

classified into two groups (1 1). The first group is expressed

Transcription of late genes is inhibited by PAA or CHX.
More than 30 h is required for the transcrlPtS tO appear after

8 ‑ 13 h after chemical induction. K3, K8, K4 (VMIPIII), K2

chemical stimulation, and the maximum amount of transcnpts(viral IL6 【vIL‑6]) and K7 (Tl. 1 , PAN‑RNA) are included in

is obtained 48 h aRerwards. Genes encoding s廿uctural proteins

this group. The second group appears slightly later. This group

includes ORF02 (VDHRF), ORF70 (thymidylate synthase),belong to this category, e.g., ORF65 (a minor capsid protein)
and ORF26 (also a capsid protein). ORF36, a serine‑protein

K6 (VMIP‑Ⅰ), ORF74 (viral G‑protein coupled receptor

kinase, is also classified as a late protein (24).

2.3.4 Latent genes【vGPCR]), K12 (TO.7), ORF16 (vBc1‑2), ORF59 (processivity

A latency‑associated gene cluster has been identifiedin
HHV‑8. This cluster includes K13 (ORF71), ORF72 andfactor, PF‑8) and ORF73 (latency‑associated nuclear antigen

lLANA])‑lytic product･ Generally, these early proteqs, includ‑

ORF73 genes, and is transcribed by two mRNAs(25). The

lng DNA replication‑associated enzymes, are assoclated withviral replication or optlmization of microenvironments. Some

ORF73 protein (LANA, LNA, or LNA‑1) is expressedofHHV‑8‑encoded cytokines or oncoproteins, including vIL‑

6 (K2), vMIPs and vIRFs, also belong to the early‑late geneconstitutively as a dot‑like stalnlng Pattem in HHVl81infected
cells regardless or TPA stimulation (Fig. 4B). LANA andgrOupS･

HHV‑8 DNA have been shown to c0‑localize in the dots or

The K8 protein is a homodimerizlng protein with ainterphase nucleiandmitotic chromosomes (26). This evidence

prototypic basiclleucine zipper (bZIP) domainat the C‑terminal

suggests that LANA tethers HHV‑8 DNA to chromosomes139Table 1. HHVl8 Open reading frames (ORFs)
ORFs

Other

Names

Kinetics

Function(Putative)

ORF4(Complement binding protein)

0RF6(SSDNA binding protein)

0RF7(Transport protein)

0RF8(Glycoprotein)

Other

Information

References

ORF10
0RFll

(DHFR)(Thymidylate synthase)

ORF17
0RF18
0RF19

(Capsid protein)(Tegument protein)

0RF20

0RF2 1(Thymidine kinase)

0RF22( Gl ycoprotei n)

0RF23
0RF24
0RF25

(Capsid protein)

ORF27

0RF28
0RF29b(Packaging protein)

ORF30

0RF31
0RF32
0RF33

0RF29a(Packaging protein)

ORF34
0RF35
ORF37

(Alkaline exonuclease)

0RF38

0RF39

(G 1 yc oprotei n)

0RF40(H eli case‑primase )0RF41(Helicase‑primase)

0RF42
0RF43

(Capsid protein)

0R F440RF45(H e li c as°‑primase)lE

Immediate early transcnpt

0RF46(Uracil DNA glucosidase)

0RF47(G 1 ycoprotei n)

(12)

0RF48
0RF49

140

Table 1 ‑Continued
ORFs

Other

Names

Kinetics

Function(Putative)

Other

Information

References

ORF52
0RF53

(DNA replication protein)

Homologue of EBV M protein

Homologue of a transactivator of EBV

lh Rc]A (p65) and p300

ORF60

(Ribonucleotide reductase)

0RF61(Ribonucleotide reductase)

0RF62(Assembly/DNA maturation)

0RF63(Tegument protein)

0RF64(Tegument protein)

ORF66

0RF67

(Tegument protein)

0RF68(Glycoprotein)

0RF69

Homologue of humanOXl2

ORF75(124, 150)

LAM P
Demonstration ofviral strain variability.

(1 3 1, 150, 204, 205)

'Gray columns indicate that the functions ofORFs were reported. This table was based on the table by Russo etal(10).

during mitosis which allows the segregation of HHV‑8

HHV‑8 related diseases. In particular, IL‑6 is仙ought oras

episomes into progeヮy cells (26)･ The LANA protein associates

the key protein in the pathogenesis of KS. VIL‑6 was shownwith the p53 proteln tO inhibit the activity orp53, thereby

to be functional by B91Cell proliferation assay (28) and topreventing apoptosis of HHV18‑infected cells (27).

activate the signahng pathway of human IL‑6 (hIL‑6) (29).

In addition, it was demonstrated that VIL‑6 induces theexpression of vascular endothelial cell growth factor (VEGF)

2.4 HHV‑8‑encoded cytokines and oncoproteins
A distinct feature ofHHVl8 is that it encodes some hom0‑

resulting in neoangiog?nesis (30)･ lt is possible that VIL‑6

10gues to human transforming Or regulatory proteins andcontributes to the induct10n OfhIL‑6 in infected cells because

cellular cytokines in its genome. HHV‑8‑related diseases suchof the high level ofhIL‑6 in the culture supematant ofHHV‑

as KS, primary effusion lymphoma (PEL) and multicentric
Castleman's disease (MCD) have been believed to be associ‑ated with the cytokine network. It is probable that HHV‑8

demonstrated that VIL‑6 signals were different from hIL‑6

plays some role in the alteration of the cytokine network to

an important role in the pathogenesis of KS; we, however, do

8‑infected PEL cell lines. On the other hand, recent studies
signals in vitro (3 1‑34). These血ta suggest that VIL‑6 plays

cytokines. In addition, viralcytokines are sometimes synergic

not consider vIL6 to be only an analogue ofhIL6.
HHV‑8 encodes three types ofMIPs, i.e., vMIPll (K6), ‑2

withviral oncogenes. The relationship is complex and remains(K4)and ‑3 (K4. 1 ). ¶leSe Chemokine‑homologues mayinduce

optimize the microenvironment fわr cell growth uslng Viral

angiogenesis and inhibit T cell responses (35). In addition,

unclear to date.

2.4.1 Viral cytokines
Amongviralcytokines encoded by HHV‑8, K2 (VIL‑6) is

K3 and K5 also contribute to the suppression of the responseofT cells by downregulating major histocompadbilityComplex

one or the most important proteins in the pathogenesis of(MHC) class I in HHV‑8 infected cells (36).
141

in all these experiments. Because a previous report suggested

2.4.2 Viral oncoproteins
The transfbmation activlty Or HHV‑8 has been demon‑that peripheral blood a cells play the role ofa reseⅣoir (55),strated by an infection experiment using endothelial cells (3 7,cell‑mediated (cell‑toICell) transmissi.on may be predominant38). Therefわre, it is unequlVOCal that HHV‑8 has transfbma‑

in vivo. Therefore, further studies uslng Cell‑mediated trans‑

tion genes.

mission are needed to clarify the HHV‑8 transmission･

Viral‑cyclin D (ORF72) inhibits the activity or retinoblas‑
toma protein (Rb), which regulates the Gl phase to S phase

3. Diagnosis of HHV‑8 infectionof the cell cycle (39), whereas LANA can interact with the

3.l PCRp53 protein and inhibit the transcript10mal activity mediatedSince HHV‑8 was discovered as DNA fragments from KS,

by p53 (27). Both LANA and v‑cyclin D are latent proteins
which are expressed constitutively in HHV‑8‑infected cells
such as KS spindle cells (40‑42). Thus, HHV‑8 encodes

detection of HHV‑8 in KS tissues. The first‑discovered

proteins regulating the actlVlty Orp53 and Rb, which are two

KSBam3302,, region ofHHV‑8 (a 233‑bp sequence in theSouthem blot hybridization and PCR were first used for the

330‑bp fragment, one of the BamHI DNA fragments) was

key proteins in tumor‑suppressor pathways･

vGPCR (ORF74) is another regulatory protein encoded byoften employed as a target gene for PCR (1). PCR using these

HHV‑8 (43,44). Transfection of VGPCR to NIH3T3 cells
resultedinthe transformation, and inocu)ation oftransfectants

prlmerS is highly sensitive and the HHV‑8 genome has been
detected in specimens from patients with various diseases

including KS, sarcoidosis, MCD, body cavity‑based lymphoma

in severe combined‑immunodeficiency (SCID) mice resulted
in KS‑like lesiPns at inoculation sites (44)･ Notably,.spindle(BCBL) (or PEL), various skin lesions (e･g., squamous cell
carcinoma, and seborrheic keratosis), and multiple myeloma.

cells in the lesions Strongly express VEGF, suggestIng that
VGPCR induced the expression ofVEGF in the transfectant

However, PCR results included obviously false‑positive

cells (44). KS‑like lesions were also fわrmed in the skin of

results. Today, evidence shows that HHV‑8 infection is associ‑

VGPCR‑transgenic mice (45). These data suggest that VGPCR

ated with only a limited number of diseases.

plays a central role in the pathogenesis of KS.
Latency‑associated membrane protein (LAMP) is another

3.2 Histological detection of HHV‑8

candidate for the HHV‑8‑encoded oncogene (46). LAMP is

HistologlCal detection of HHV‑8 appears to be di爪cult･

encoded in the genome reglOn from ORF75 to TR, whichcontains the K15 gene. This protein has 12 transmembrane
domains and is homologous to LMP2A ofEBV. Thefull trans‑
formation activity and interaction with TRAF‑1 , 12 and l3

Because quantitative PCR revealed only a low copy number(nearly single copy) ofHHV‑8 in KS, an in situ PCR method
was employed to detect the HHVl8 genome (56)･ Howev.er･

were reported (46).

the precise loca)izat10n Of this vlruS. Today, the most sensitive

its sensitivity and specificity w守re not suWICient to determlne

and convenient histopathologlCal me血od or detectlng HHV‑8

Viral Bcト2 and viral FLICE‑inhibitory protein (VFLIP)
Were demonstrated to inhibit apoptosis (47,48). On仇e otheris immunohistochemistry uslng the antibody agalnSt thehand, viralinterferon regulatory factors (vIRFs) were shown

ORF73 protein (LANA), one of the latent proteins of HHV‑

to inhibit theinterferon signaling pathway (49‑5 1 )I However,
it is noteworthy that these proteins are classifiedintothe lyticclass ofviral proteins. Considering that most HHV‑8‑infectedsuggesting that all these cells are latently infected with HHV‑

cells are in the latent phase, these lytic proteins can have noantlgensWere developed, however, these antigens were rarely

major role in the pathogenesis of HHV‑8‑associated malig‑

e.xpressedinHHV‑8‑associated diseases (58)･ ln situ hybridiza‑

nanCleS.

t10n tO detect the TO.7 and Tl.1 genes which are the latent

8. Most KS or PEL cells are positive fわr the ORF73 antlgen,

8 (Fig. 3,4) (41,42,57). Several antibodies against lytic

and early genes of HHV‑8, respectively, was also used, but
the expression levels of these genes are low in KS lesions.

2.5 Experimentalinfection in vitro
HHV‑8 transmission was first reported uslng 293 cells

3.3 Serology(transfbmed human kidney cell line) but with a very low
efrlCiency (52). Thus far, an efficientviral propagation system
is not available except through the use of HHV‑8‑positive

8‑infected individuals. The seroprevalence ofHHV‑8 has beenAnti‑HHV‑8‑antibodies can be detected in the sera ofHHV｣

lymphoma cell lines in combination with chemical stimula‑found to vary between studies, depending on the type of assaytion using TPA or n‑butylate. The transmission of HHV‑8 toemployed and the countries where the investigations wereendothelial cells has been investlgated in vitro by several

carried out (59‑67). To date, two methods, immunofluores‑groups (37,3 8,53 ,54). Dermalmicrovascular endothelial cells

cence assay (IFA) and enzym6‑linked immunosorbent assay(DMVECs) transfected with the human papillomaviruS (HPV)
E6 gene were effectively infected with HHV‑8 by exposure(ELISA), have been used to detect antibodies against HHV‑
8. However, the target antlgenS differ for each method. ln
IFA, LANA corresponding to the ORF73 protein is the major
antigen; in ELISA, ORF59 (PFl8), ORF65 (a minor capsid

to cell‑free supematants derived from TPA‑treated BCBL‑ 1 ,an HHV‑8‑infected PEL cell line (38). About 5% ofHHV‑8l
infected DMVECs spontaneously expressed ORF59, a lytlCprotein), ORF26 (another possible minor capsid protein),
ORF73 (LANA) Or a lysate ofwhole viral particles have beenproteinofHHV‑8, 8 weeks afterinfection, while LANA wasmorphologlCalchanges and also displayed a transformation

used as antigens (60,61, 65171). The use of these different
antlgenS Seems tO have caused discrepanciesindata reported

activity showing the loss or contact inhibition and growth inso far (65). Recently, it was shown that lytic proteins such assoft agar (3 8).Another group reported that highly concentrated

ORF 65, K8.1A and K8.1B, and the latent ORF73 protein
exhibited high reactivitywith the sera of HHV‑8‑seropositive
individuals as detemined by Westem blot analysis (21 ,69).
Based on these results, ELISAs, uslng ORF59, ORF65,

expressed in 80% (38). HHV‑8‑infected DMVECs exhibitedviralparticles derived from the supematant ofTPAIStimulated
BCBL‑1 is required for transmission ofHHV‑8 to other types

ofendothelial cells (54). Thus, HHV‑8 can infect endothelial
cells in vitro; however, cell‑free transmission was employed

K8. lA, K8. 1B and ORF73 antlgenS and with high detection

142

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Fig. 3. Kaposi's sarcoma.
(A) HE staining. (B) Immunohistochemistry of ORF73, a latent protein. (C) Immunohistochemistry ofORF59, a lytic protein.

Fig. 4. Primary emlSion lymphoma (PEL).
(A) Giemsa staining of an HHV‑81infected PEL cell line 'TY‑1 '.
(B) Immunofluorescence assay ofHHV18･ Serum derived from a Kaposi'S sarcoma patient was used as the primary antibody.
Dot‑like signals orLANA were fわund in the nuclei ofTY‑1 cells.

143

(A)

Fig. 5. Multicentric Castleman's disease (MCD).
(A) HE staining. (B) Immunohistochemistry of ORf73. (C) Immunohistochemistry of K8, a lytic protein･

sensitivity, were developed (69).

such as Uganda (35 ‑ 53%) (Table 2). Generally, sera derived
from KS patients are positive for HHV‑8antibodies regardlessof HIV infection. The homosexual population exhibits a higher

4. Epidemiology

level of positivity than the heterosexual one･The transmission modes of HHV‑8 have not yet been

4.1 Seroprevalence and transmission

Current HHV‑8 antibody testlng has some problems intens of accuracy, as previously described, particularly inclarified. In countries with an endemic infection, horizontaltransmission among chil血en is thought to be Prevalent (63),patients with asymptomatic HHV‑8 infection (65). However,while sexual transmission appears to play an lmpOrtant roleseveral groups have reported the seroprevalence of HHV‑8 inamong homosexual men in non‑endemic countries (75)･

the general population of various countries (Table 2). Positivity
in these studies has varied from 0 to 53%, depending on the

Recently, a large cohort study of Amsterdam homosexuals

revealed that seroconversion of the antibodies agalnSt HHV

assay used and the countries where research was conducted

8 is associated with orogenital contact, and this study also(60, 63, 69, 72‑74). Infection with HHV‑8 seems to be

indicated that the titer of the antibody against ORF65 increases

uncommon in血e United States (U.S.) (0 ‑ 25%), Japan (1.4%)

in HIV‑seronegative homosexuals but that agalnSt ORF73
increases earlier than that agalnSt ORF65 in HIV‑infected ones

and Northem Europe (3 ‑ 5. 1%), common in certain Mediter‑
ranean countries (4 I 12%), and prevalent in Ahcan countries(7 1). The shdy also revealed that orogenital sexual behavior

Table 2. Seroprevalence of HHV‑8Prevalence

MethodAntigen
HIV+/KS+PEL cell (LANA) (67,HIV+/KS‑

67‑88 %

12‑56%

206, 207)

HIV‑/KS+

51‑94 %

Hemophilia; 0‑3 %(67)

STD; 28%(206)

Population

0‑12 %(lyticPEL(LANA)

ORF65

ELISA

phase)(208)

(84)

80

83‑96

%

(166)

%
18

89%

61‑69

%

donor

0‑5 % (USA)

1 % (women)(62)

0.2 % (Japan)(72)

53% (Uganda)(67)

4 % (Italy) (207)

3% (UK)(67)

Homosexual; 30%(207)

WB

Blood

100

%

20‑28

%
20%

ORF26 (peptide) (61)60%

ORF65 (66)

92%

24%

Whole vims lysate (60)

92%

26%

93%

PEL, ORF65(67)81.5%

30‑31 %

94%

0

%

11

%

%

27%

C omb ination

IFA, ELISA

0‑5 %(USA, UK)
33‑52%(Uganda)(63)

IPA, ELISA, WB PEL, ORF65(64)Mixed ELISA, &ORF65, K8. 1, ORF59,IFA,(LANA)WB

ORf73

PEL(69)30% (homosexual)

96%

63.6%(sexual)
0%(hemophilia)

144

2 1 % (homosexual)100%

1.4%(Japan)

43% (Uganda)(63)was usually ̀unprotected'unlike the anogenital sexual inter(OSM) and tumor necrosis factor (TNF)‑alpha, were shown

Course among Amsterdam homosexuals examined in thereport. Taking into consideration the high copy number ofto be required for the growth of KS cells in vitro･ Amongthe vims in saliva compared with that in semen (76), it iscells. HHV‑8‑encoded vILl6 is detected in tissues of KS
lesions. A recent report revealed that vIL16 Could stimulate
the signaling pathway of human ILl6 (29); therefore, HHV‑8
is probably associated with the fbmation or the cytokine
network in KS lesions.
SerologlCal evidence also supports the association ofHHV‑

them, IL‑6 isknOwn to be an important growth factor of KS

clear that saliva一mediated transmission is possible.

4.2 MolecuIarepidemiology
HHV‑8 genomes are classified into several subgroups basedon the sequence variability of the Kl gene (77,78)･ Ther? are
two hypervariable reg10nS in the Kl gene･ The two reglOnS

8 with KS pathogenesis.Anti‑HHV‑8 antibodies were detectedencode the extracellular domain of the Kl protein, and thesein almost all sera derived from KS patients (69). In addition,

variations are classified into at least four groups, i.e., A, B, C

homosexual males w仙AIDS, who belong to a group at highand D. Subtype A was mainly detected inAlDS‑KS patientspatients of Pacific Island descent･ The geographical differencesin HHV‑8 infection may renect the history of migration ofhuman populationsfrom Afhca over the past 35 ,000 to 60,000

risk for KS, exhibit high seroprevalence of the antibody
agalnSt HHV‑8･ Seroconversion of the antibodies agalnSt
HHV‑8 was observed before the appearance of KS lesions inboth AIDS and organ‑transplanted patients (70,7 1 ,84,85).
These data indicate the specific relationship between KS andHHV‑8 infection.
The mechanism of KS regression has been investlgated.
HHV‑8‑specific cytotoxic T lymphocytes (CTLs) against

years (77).

HHV‑81K12, K8･ 1 and Kl proteins yere identified (86)･ We

in the U.S., and subtype C was predominantly fわund inpatientswith the classic KS, iatrogenic and AIDS‑KS in the
Middle East and Asia. Subtype B was fわund in KS patientsof African descent. Subtype D was rare and found in KS

reported one case orKS regression, ln Which the depletion or

HHV‑81infected cells was observed in the process of sponta‑
neous regression (87). In this case, many CD8‑positive CTLs
infiltrated the KS lesions (87)･ These findings Puggest thatCTL response plays a central role in the regression OfKS.

5. HHV‑8 related diseases

5.1 Kaposi's sarcoma (KS)KS was first described in 1872 as a rare tumor occumng lnelderly men of Mediterranean descent (classic type) (79)･
5.2 Primary effusiorL lymphoma (PEL)

Recently, three additional climical types, whichare histologicallyindistinguishable, have been recognized: AIDS‑associated,
post‑transplantational (iatrogenic or immunodeficient) andPEL is a new disease entitydescribed by Nador et al (88)･
Thistype of lymphoma appears as lymphomatous effusions

A飢can (endemic)types (80). Skin lesions of KS are clinicallyoccurrlng in the absence of a contlguOuS tumor mass. These

classified into patchy, plaque and nodular stages･ In the patchy

efhsions exhibit a distinctive morphology bridging large‑cellstage, small red flat lesionsare noted onthe skin. These lesions
fuse together to formplaque lesions(plaque stage) and later

irrmunoblastic lymphomas oranaplastic large‑cell lymphomas(ALCLs) (Fig. 4A). Genetically, HHV18‑associated lymphoma

become brown nodular and elevated lesions in the nodular

cells lack c‑myc gene rearrangements and bcl‑2, ras and p53

stage. These skin lesions appear mainly on the extremities

gene alterations (88). A recent study revealed that frequent

but in more advanced cases叩pear aS multiple ovoid‑sh叩ed

mutations in the bcl‑6 gene were detected in PEL cells,

skin lesions distributed symmetrically overthe trunk. Organ
and/Or the lungs, resulting in death. HistologlCally, thesuggestlng that PEL cells originatefromthe germinal center or
the post‑germinal center B cells (89). TYleir immunophenotypes
are undetermined, i.e., CD45 (+), CD138 (+), B cell markers

proliferation of spindle cells with slit‑like vascular spaces is(‑), and T cell markers (‑); however, an immunoglobuline

characteristically obseⅣed (Fig. 3A).

gene rearrangement was detected (88, 90)･ These lymphomas

involvements are sometimes observed in gastrointestinal tracts

occur in HIV‑infected homosexual males, which is the same

KS had been suspected to be an infectious disease because

as 冗.S occu汀enCe.

of the fわllowing reasons. 1 ) AIDS‑KS occurs particularly inhomosexual males･ 2) The progression of KS depends on the

In 1995, HHVl8 was first detected in AIDS'‑associatedhost's Immune Sta仙s, and spontaneous regression of KS is

BCBL (PEL) (83). PEL cells contain a high copy number

sometimes reported. 3) The geographic distribution of KS in(40‑100 copies/cells) of HHV‑8 DNA (83)･ PEL cells are

the world is restricted to certain regions. Prior to the identifi‑

sometimes coinfected with EBV, while others are infectedcation of HHV‑8, whenever any viruses were detected in KS

onlywith HHV‑8. However, expressions ofLMPs and EBNAs

patients, they were assumed to be infectious agents of KS.

are suppressed in PEL cells. Several HHV‑8‑infected cell lines

Therefore, the discovery of HHVl8 Completed the search forhave been established from PEL cells (2,5,9 1‑95). We estab‑lished an HHV‑8‑positive and EBV‑negative cell line, TY‑ I ,etiological and infectious agents of KS. DNA fragments of
HHV‑8 can be detected in 95% of KS tissues by PCR regard‑
less of their clinical subtypes (81,82). However, the copy
number of this virus in spindle cells in KS tissues is loweven from EBV‑positive and HHV‑8‑positive PEL cases (9 1 )･
These data suggest that HHV‑8 plays an essential role in thepathogenesis of PEL
Studies of the HHV‑8‑positive PEL cell lines have provided(approfimately 1 copy per cell) (83)･ It has been demonstrated
by varlOuS me仇ods that almost all spindle cells in KS tissues

insights into the features of this virus･ It has been demon‑

are in the latent phase (41,42,57) (Fig. 3 B). The expression ofstrated that all orthe PEL cells express LANA, (Fig. 4B),

lytic proteins is limited in KS lesions (Fig. 3C). Therefore, it
is hkely that latent infection with HHV‑8 is important for thesuggestlng that they are in the latent phase･ It has also beenpathogenesis of KS.

cell lines from the latent phase to the lytic phase (2)･

shown that chemical stimulation uslng TPA converts the PEL

Some types of cytokines have been detected in the sera ofElectronmicroscopy has revealed that many HHV‑8 particles

KS patients at high levels, and several of them, including

are found in the nuclei ofTPA‑treated cells (5) (Fig. 1). The

beta fibroblast growth factor (bFGF), IL‑6, 0nocostatin M

fact that PEL cells produce IL‑10, IL‑6 and the receptors for145IL‑6 suggests the presence of an autocrine loop for growth,

produced HHV‑8‑positive and EBV一megative tumors in thewhich is the same as that of KS (96). Among HHV8‑encoded

proteinS, K9 (VIRF) isknOwn to inhibit the interferon signaling

hoculated sites, while the tumor cells exhibited morphologl‑
cal characteristics similar to those ofALCL. These fhdings

pathway, and this suggests that K9 functions as an oncogene
in PEL cells (49). However, the expression of K9 protein isand that they can have an anaplastic large cell mo叩hology.

suggest that HHV8 may be associated with solid lymphomasclarify the oncogenic role of HHV‑8 in the pathogenesis of

The lymphomas should be distinguished from classical
ALCLs that are defined by the REAL classification evenPEL

though their morphology and part of their immunophenotype

restricted in PEL cells. Thus, further studies are required to

mimic the classical ALCLs.

5.3 Multicentric Castleman's disease (MCD)MCD is a rare disease characterized by plasmacytlC

5.5

0thersDNA fragments of HHV‑8 have been detected in certain
diseases; however, the associations or HHV‑8 With these
diseases need to be elucidated. Rettig et al. reported that HHV‑
8 DNA was detected in bone marrow dendritic cells frommultiple myeloma. patients ( 1 14)･ However, there were both

lymphadenopathy with polyclonal hyperimmunoglobulinemia

and high levels of IL6 in the serum (97‑99). Follicular
hyperplasiawith proliferation of plasma cells and hyalhe
vascularalterationsin the lymph node are the histopathologicalhallmarks of MCD (Fig. 5A). In 1996, HHV‑8 was firstdetected in some cases ofMCD (100). Unlike in cases of KS

positive and negatlVe reports using PCR (1 1 5‑1 19) and ser0‑
logical techniqu.es (120,121)･ Considering these papers, aand PEL, the HHV‑8 genome is detectedinonly a small popula‑tion ofMCDs. However, HHV‑8 DNA isfrequently detectedin

definitive association of HHV‑8 with myeloma cannot be

tissues obtained from patientswith MCD associated with HIV

made. HHV‑8 DNA was also detected in lesions ofsarcoidosis

infection (1 00‑ 102). Recently, HHV‑8 wasalso detected witha high fTrequency in MCD complicated with polyneuropathy,organomegaly, endocrinopathy, M protein, and skin changes

patients (1 23); however, all these.results are considered to be(1 22), Bowen's disease and various skin lesions ortransplant

either false positives or not assoclatedwith the pathogenesisof the diseases.

(POEMS) syndrome (103).
Immunohistochemical studies revealed that HHV‑8
infected cells are localized in the mantle zone of deformed

6. Conclusion

lymphoid follicles and that the lytlC and latent proteinsencoded by HHV‑8 are e.xprFssed in these cells (58, 104) (Fig･
5B and 5C)･ Lytic protelnS Including VIL‑6 are also strongly

Since the discovery of HHV18,virologlCal and molecularcharacteristics of HHV‑8 have been studied extensively andexpressed in MCD (58,102, 104) (Fig. 5C). These data suggestthat the role ofHHV‑8 in MCD differs from that in KS or
PEL Whether or not HHV‑8‑encoded VIL‑6 plays a role inthevirus DNA was determined within only two years a洗er its

actively. It was surpnslng that an almost complete sequence of

discovery. Cu汀ently, epidemiologlCal and histopathologlCal

studies are ongolng, Canted out by many researchersinvarious
countries, which will elucidate the pathogenesis of HHV‑
8‑associated diseases. Thus, HHV‑8 has become one ofdle extensively studied viruses in the world. However, its

the proliferation of plasma cells is an important issue inelucidating the pathogenesis of HHV‑8‑associated MCD,
since the level ofIL‑6 is high in the sera of patients with

MCD.
Recently, Dupin et al. reported that HHVl8 was detected inoncogenesity and its associationwith the pathogenesis of KS,

plasmablasts of the plasmablastic variant ofMCD ( 1 05). They

which are the focus of HHV‑8 studies, have not been clarified

also demonstrated that plasmablasts have a clonal lambda

as well as for other oncoviruses such as EBV, HPV, and humanlight chain and proposed that the plasmablastic lymphoma

T‑cell leukenTia yiruS‑ 1 (HTLVl 1 )I In this reviey, We suggest

associated with MCD is a new disease entlty Which is alsothat latency lS Significant for the pathogenesIS Of HHV‑8‑
associated malignancies. Virologically, the most slgnificant
issue in HHV‑8 research is that permissive cells that rephcate

associated with HHV‑8 infection.

5･4 AIDS‑aSSociated anaplastic large cell lymphoma

very emciently have not yet been fわund. Therefわre, it isdifficult to perform infecdon experiments or to produce mutant(ALCL)
TYle existence ofAIDS‑associated ALCL has been discussed
by some authors (106‑1 1 1). However, the diagnostic criteria
for ALCL are ambiguous and confusing in these reports. Thereis a general consensus that ALCL exhibits the fbllowlng

protein in the vims.

histopathological features: 1) anaplastic large blastic cellmorphologywith occasional horse‑shoe‑shaped/multiple

concems vims transmission. Recently, mass cohort studies

nuclei and one or two prominent nucleoli; 2) much larger

have been reported; however, major transmission modes

cells than those found in ordinary large cell lymphomas, Withremain unclear, particularly in countries where the virus isviruses. The function of each viral protein will be investi‑
gated uslng tranSgenic mice or transfection studies; however,mutant viruseswill be needed to investlgate the role of each
Another important aspect of HHV‑8 studies in the future

a greater cytoplasmic volume; and 3) growth in a cohesive

endemic. Studies on the natural history of HHV18 infection

sheet‑like pattem (112). ALCL is classified as a T/null cell

will be essential to the HHV‑8 research.

typelymphoma according to the revised European‑Americanclassification of lymphoid neoplasms (REAL classification)

ACKNOWLEDGMENTS(1 12). Meanwhile, reported ̀AIDS‑ALCL'contained bo仇B

The authors thank Ms. Yuko Sato and Eiko Moriishi for
their excellent teclmicalassistance. We also thank Drs. Takeshi

and T cell lymphomas.

We reported three cases of AIDS lymphoma with ananaplastic large cell morphology. Notably, all three cases were

Kurata and Takuya Iwasaki (NationalInstitute of Infectious

infectedwith HHVl8 (1 1 3). The cases were complicatedwith

Diseases) for their collaborative efforts. We are grateful to

KS, PEL and MCD. In addition, We demonstrated thatDrs･ Aikichi Iwamoto (Department of Infectious Diseases,

subcutaneous inoculation of SCID mice with PEL cells

Institute of Medical Science, the UniversityofTokyo), Natsuo

146

Tachikawa (AIDS Clinical Center, International Medical

12. Zhu, F.X., Cusano, T. andYuan, Y. (1999): Identification

Center orJ叩an) and to many physicians and pathologists fわrof血e immediate‑early transcnpts of Kaposi 's sarcoma‑

supplying specimens and clinical data. We are also gratefulto Dr. Shigeo Mori (Division or Molecular Pathology,

13. Lukac, D. M., Kirshner, ∫. R. and Ganem, D. (1999):

Department of Cancer Research, Institute orMedical Science,

TranscnptlOnal activation by the product of open reading

the University of Tokyo) for the helpful suggestions. This

frame 50 of Kaposi's sarcoma‑associated herpesvirus

study was supported by a grant‑in‑aid for Scientific Researchis required fわr lytic viral reactivation in B cells. ∫. Viro1.,

associated he叩eSVims, J. Viro1., 73, 5556‑5567.

from the Ministry of Health and Welfare, Japan.

73, 9348‑9361.

14. Seaman, W. T., Ye, D., Wang, R. X., Hale, E. E., Weisse,
M. and Quinlivan, E. B. (1999): Gene expression from

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