K. Hayashi

b

a

c

d

e

f

g
P 1

h: PCR for HVP- EBNA1

2 3

4

5

6

7

N N

389 bp –Fig. 4. Baboon-EBV (HVP)-induced lymphoproliferative diseases with hemophagocytosis in rabbits. Rabbit nasal
bleeding due to bleeding tendency (a). Splenomegaly (b) and lymph node swelling with hemorrhage (c). Atypicallymphocyte infiltration and marked hemophagocytosis in lymph nodes (hematoxylin and eosin stain) (d) and HVPEBER-1 (in situ hybridization) (e). Atypical lymphocyte infiltration in the liver (hematoxylin and eosin stain) (f)and HVP-EBER-1 (in situ hybridization) (g). (h) Detection of HVP-EBNA1 DNA by PCR. HVP-EBNA1 DNA wasamplified in the positive control (lane P) and HVP-infected rabbit tissues (lanes 1 through 7) but not in the negative
controls (lane N).

50

EBV-associated diseases and their animal models

PCR for the HVP-EBNA-1 region was carried out using the primer pair HPNA-1S: 5'-CTG
GGT TGT TGC GTT CCA TG-3' and HPNA-1A:
5'-TTG GGG GCG TCT CCT AAC AA-3'. Amplified DNA of the expected size of 389 bp was demonstrated in the positive control (594S) and 594S
(HVP)-induced rabbit LPD lesions (Fig. 4h) as
well as in peripheral blood from the infected rabbits. PCR analysis revealed the presence of HVPDNA in all six rabbit cell lines established from
HVP-infected rabbits. Clonality analysis using the
HVPTR2 probe revealed monoclonal or oligoclonalbands in 594S (HVP)-induced rabbit LPD lesions(data not shown).
On the latency of EBV infection, whilecross-reactive EBNA-2 expression by immunofluorescence test was detected in 594S cells, neither
EBNA-1 nor LMP-1 cross-reactivity was observed.
HVP-EBNA1 and HVP-EBNA2 mRNAs were detected by reverse transription-PCR in 594S cells
and HVP-induced rabbit LPD lesions, suggesting
the latency type III. HVP-LMP1 transcripts weredetected in 2 of the 4 in vivo samples. However,
reverse transription-PCR revealed mRNA expression of both HVP-EBNA1 and HVP-LMP1 but
not of HVP-EBNA2 in rabbit T cell lines (data notshown), suggesting the latency type II.
I consider that this rabbit model of fatal LPD
with VAHS induced by primary infection of HPV
is a useful animal model for fatal childhood EBVAHS (Kikuta et al., 1993; Su et al., 1994, 1995;
Chen et al., 1997). Those results mentioned above
suggested that the clinicopathologic features of the
rabbit model were similar to those of fatal childhood EBV-AHS described by Su et al. (1994,
1995).
To determine the nature of HVP-induced rabbit LPD, it is important to determine if the atypical lymphocytes in rabbit LPDS were reactive or
neoplastic, that is, whether or not they exhibitedclonal cytogenetic abnormalities. Both oligoclonal
and monoclonal expansion of HVP-infected rabbit
lymphoid cells in rabbit LPD in vivo was observedby Southern blot analysis of EBV termini. How-ever, chromosomal analysis revealed normal rabbit
karyotypes in cells from all 10 in vivo LPD lesions
from 5 rabbits examined, and in 5 of the 6 IL-2
dependent rabbit cell lines (Hayashi et al., 2003a).
This suggested that most in vivo rabbit LPD cells
were non-neoplastic in nature. In addition, the rabbits with HVP infection usually died within a shorttime of VAHS. Based on these results, it is possible that most HVP-infected rabbits die relatively
quickly of severe LPD and VAHS with bleedingin the presence of oligoclonal LPD, before the development of completely monoclonal neoplastic
lymphoma. However, it is also possible that these
rabbit LPD lesions may contain some small components of neoplastic or pre-neoplastic cells with
HVP infection.
Therapeutic trials with vidarabine or CHOP*
for a rabbit model of EBV-AHS were not succeeded (Hayashi et al., 2003b).

Comparative analysis of the rabbit models
with human EBV-associated LPD
Four rabbit models using simian EBV-like viruseshave been reported (Table 2). Three of them using Cynomolgus-EBV, HVMA and HVMNE are
animal models for human EBV-associated malignant lymphoma. Cynomolgus-EBV- or HVMNEinduced rabbit malignant lymphoma showed T-cell
phenotype, while phenotype of HVMA-induced
rabbit malignant lymphoma was not determined. It
is very interesting that Cynomolgus-EBV (Si-IIAEBV and HVMF1) and HVMA were isolated fromthe simian cell lines infected with retroviruses suchas HTLV-II, SIV or STLV, respectively. Amongthese three viruses, Cynomolgus-EBV can induce
rabbit lymphoma the most frequently (90%) andis the only one kind to be demonstrated to transmit to rabbits by natural peroral infection and toresult in rabbit lymphoma development. The latency type I/II of Cynomolgus-EBV induced rabbit
T-cell lymphoma is compatible with that of human
EBV-associated T-cell lymphoma. However, sim-

* CHOP, combination chemotherapy consisting of cyclophosphamide, hydroxydaunomycin, oncovin andprednisone.

51

K. Hayashi

ian EBV-like viruses (Cyno -EBV, HVMA and
HVMNE) infection of rabbits resulted in T-cell
lymphomas several months of latent period after
primary infection, while the latency period between the primary EBV infection and human EBVassociated T-cell lymphoma development is considered more than 30 years. The direct causative relation between primary simian EBV-like viruses andsubsequent rabbit T-cell lymphomas is very clear.
However, additional events such as some genetic
alterations must be needed to develop human EBVassociated T-cell lymphomas during long latent
infection of EBV after the primary EBV infection.
If possible, I need to develop some animal models
with long latent virus infection and subsequentT- cell lymphomas for human EBV-associatedT-cell lymphomas.
As the clinicopathologic features of HVPinfected rabbit model are very similar to those of
fatal childhood EBV-AHS with T-cell LPD (Suet al., 1994) or fulminant EBV-positive T- cell
LPD following acute /chronic EBV infection(Quintanilla-Martinez et al., 2000), I suggest that
this rabbit model of fatal LPD with VAHS, induced
by a primary natural route of HPV infection, represents an animal model for fulminant EBV-positive
T-cell LPD with VAHS due to primary EBV infection. This system may be useful for the study ofhuman EBV-AHS pathogenesis, prevention andtreatment.

multistep oncogenesis by risk factors and malignant
transformation from a single cell within the EBVinfected pool (Rickinson and Kieff, 2001). It is
generally accepted that risk factors such as genetic
background, ethnicity, environmental factors including nitrosamines in foods, economic status andmalarial or helicobacter pylori infection and themutation or deletion of genes like p53 are needed
for the development of the other EBV-associatedtumors. EBV contributes to the malignant phenotype, such as growth in low serum concentration, anchorage-independent growth in soft agar,
and tumorigenicity in nude mice (Shimizu et al.,1994), and oncogenic role of EBERs and resistanceto apoptosis by EBERs are also demonstrated in
Burkitt’s lymphoma cell line Akata (Komano et al.,
1999; Ruf et al., 2000). Insulin-like growth factor
1 induced by EBERs acts as an autocrine growth
factor for EBV-positive gastric carcinoma (Iwakiri
et al., 2003). On the other hand, there are different
hypotheses that EBV is only an innocent bystander
virus or that EBV just infects the tumor cells after
the malignant transformation of EBV-non-infected
cells and EBV does not contribute to the oncogenic
process (Ohshima et al., 1998).
The direct causative relationship between
infection by EBV-related virus and the subsequent development of malignant lymphoma is veryclear in this rabbit experimental model by EBVrelated virus, reinforcing the assertion that EBV
has the significant role in the development of EBVassociated tumors. According to the comparative
overview data of EBV-associated lymphomas inhuman and rabbits (Tables 1 and 2), these rabbit
LPDs induced by EBV-like viruses are very goodmodels for the fatal lymphoproliferative disease
seen in fatal infectious mononucleosis/fatal LPD
with a virus-associated hemophagocytic syndrome
and EBV-positive T cell lymphoma. In addition,
new animal models developing after long latent
infection are needed for human T-cell lymphomawith a very long latency in long-term EBV carriers.
In view of the scarcity and expense of non-humanprimates, these rabbit models are very useful andinexpensive alternative experimental models forstudying the biology and pathogenesis of EBV,Perspectives on animal models of EBVassociated diseases
In spite of the many investigations into the roleof EBV infection in the pathogenesis of EBVassociated diseases, a direct causal relationshipbetween EBV infection and these tumors has been
established only in primary EBV infection relateddiseases including infectious mononucleosis andEBV-AHS in childhood and the opportunistic
LPDs arising with a relatively short latency period
in immunocompromized hosts. However, mostEBV-associated tumors arise with a very long latency in long-term EBV carriers. This suggests the52

EBV-associated diseases and their animal models

especially in relation to human EBV-related lymphomas. Rabbit models with Cynomolgus-EBV or
HVP can also be used for studying the mechanismof the natural oropharyngeal route of infection by
EBV-related virus.
On the present animal models in vivo of EBV
infection and EBV-associated diseases, all animalmodels are useful for studying EBV-associated
LPD or EBV-related lymphomas, and most of them
are acute or subacute models with short latency anddevelop by primary virus infection. Mouse models
using murine gamma-herpesvirus is the only one
for EBV-related lymphoma with a very long latency
in long-term gamma-herpesvirus carriers. Rhesus
monkey model using LCV-naïve rhesus monkeys
infected with rhesus LCV is a very excellent one
for natural primary EBV infection and subsequentlatent EBV infection, because essentially the same
virus-host interactions have been maintained inthis system. However, rhesus LCV-related tumors
without immunodeficiency have not been detected
yet. These animal models in vivo also provide ameans of studying prophylactic regimens such asrecombinant vaccines and CTL epitope peptidebased vaccines. These are useful in vivo system
to test novel therapies including new drugs, CTLbased immune therapy and gene therapy directedagainst the EBV-positive LPD or lymphomas which
are usually refractory to conventional chemo therapy (Franken et al., 1996; Barnes et al., 1999).
However, it is noteworthy that there have been no
animal models in vivo for EBV-infected epithelial
tumors such as a set of nasopharyngeal carcinoma
or gastric carcinoma, because the cases of EBVassociated gastric carcinoma (6.7% or 4.7–11.2%
of gastric carcinoma cases) (Tokunaga et al., 1993;
Koriyama et al., 2001, respectively) is the largest in
number among EBV-related tumors in Japan. To
elucidate the detail pathogenesis of EBV-associateddiseases using animal models, sequential follow-up
studies and clarifying functions of the oncogenesof EBV or EBV-like viruses are needed. Animalmodels infected with defected EBV-like virus deleting some important oncogenes will be also usefulfor the function of the oncogenes. Why rabbits are
so highly susceptible to lymphomagenesis inducedby simian EBV-like viruses is not clear. I could notdemonstrate the lymphomagenesis in some strainsof mice, rats and hamsters (unpublished data). The
mechanism of cross-species virus transmission
should be elucidated.

Acknowledgments: The original works cited in this review were supported, in part, by grants from the Ministry of Education, Culture, Science, Sports, and Technology, Japan (05670193, 09470051, 11470058, 14570190,
16590314).

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Received January 17, 2005; accepted March 18, 2005
Corresponding author: Kazuhiko Hayashi, MD

56