Review
Manipulation of immune responses by EpsteinÁ
/
Barr virus
Victor Levitsky *, Maria G. Masucci
Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, SE-171 77, Stockholm, Sweden
Abstract
Epstein Á
/
Barr virus (EBV) infects and persists for life in the majority of the human population. Persistence is achieved
through a combination of strictly regulated programs of latent infection in B-cells and chronic reactivation of virus
replication in lymphoid tissue and mucosal surfaces. The resulting multiple patterns of virus Á
/
host interaction have
selected unique strategies of immune escape. T-cell mediated immunity plays a central role in the control of EBV latency
and several immune escape mechanism that protect the virus at this stage of its life circle have been characterized in
details. In contrast, the contribution of innate immunity and the immune regulation of productive infection are largely
unexplored areas that may yield important clues on the establishment and maintenance of EBV persistence. This review
summarizes well known and emerging mechanisms of EBV immune escape that may reveal new strategies of
immunoregulation and promote new approaches to the prophylaxis and treatment of EBV associated diseases. # 2002
Elsevier Science B.V. All rights reserved.
Keywords: Epstein Á
/
Barr virus; Lymphoproliferative disease; Persistence; Immune escape
1. Introduction
Epstein Á
/
Barr virus (EBV), a gamma herpesvirus
of humans, has two major target tissues in vivo, B-
lymphocytes and stratified epithelium. In B-cells,
the infection is predominantly non-productiveor
‘latent’ and leads to the establishment of a carrier
state, which is maintained for the entire life of the
infected host. Spread to new hosts is ensured by
intermittent reactivation and productive replica-
tion at epithelial surfaces. Transmission is usually
asymptomatic and only when primary infection is
delayed until adolescence or adulthood it may
cause a benign lymphoproliferative disease
(PTLD) known as infectious mononucleosis
(IM). Yet, the presence of viral DNA and the
regular expression of viral gene products strongly
implicate EBV in the pathogenesis of a broad
spectrum of malignancies. These include lympho-
mas of B, T, and NK cell origin such as the
immunoblastic lymphoma of immunosuppressed,
endemic Burkitt’s lymphoma, Hodgkin’s Disease
(HD), anaplastic large T-cell lymphoma and mid-
line granuloma reviewed in Pallesen et al. (1993),
but also lymphoepitheliomas of the nasopharynx,
thymus, and stomach (Imai et al., 1994; Leyvraz et
al., 1985) and leiomyosarcomas arising in organ
transplant children and HIV patients (Lee et al.,
1995; McClain et al., 1995). The association of at
least some of these tumors with severe immuno-
suppression stresses the importance of immune
* Corresponding author. Tel.: '
/
46-8-7286280; fax: '
/
46-8-
331399
E-mail address: victor.levitsky@mtc.ki.se (V. Levitsky).
Virus Research 88 (2002) 71 Á
/
86
www.elsevier.com/locate/virusres
0168-1702/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
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