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CORRESPONDENCE One of the intriguing and largely unexplained features of
primary Epstein-Barr virus (EBV) infection in humans is that only a
small proportion of individuals display the clinical symptoms of acute
infectious mononucleosis (IM).1 Previous studies have proposed a role for a number of potential factors in controlling the
symptoms of primary EBV infection, such as viral load and cytokine
dysregulation.2 It is entirely feasible that the dynamics of emergence of the EBV-specific T-cell response during the early stages of acute infection may delimitate the patterns of clinical symptoms in different individuals. Indeed, massive expansion of CD8+ T cells specific for EBV latent and lytic antigens,
which is often a feature of acute EBV infection, suggests that
these T-cell responses are recruited to control the active viral
infection.1-3 However, understanding the biological
significance and the longitudinal dynamics of these T cells during
acute viral infections in humans is often difficult and is complicated
by the nature of immune responses in naturally outbred individual
patients. We have addressed some of these limitations by analyzing the
dynamics of T-cell responses to a large panel of cytotoxic T lymphocyte
(CTL) epitopes in 2 HLA class I-matched unrelated human subjects
undergoing a primary EBV infection with contrasting clinical
symptoms
Further characterization of the EBV-specific CTL responses with
HLA-peptide tetramers revealed interesting dynamics during the course
of acute IM with respect to the absolute numbers and the phenotypic
markers expressed by the antigen-specific T cells. Consistent with the
ELISPOT assays, ex vivo staining with HLA-peptide tetramers also showed
that a large proportion of CD8+ T cells were specific for
an early lytic antigen during the acute phase of infection, which was
followed by a significant culling during the recovery phase (Table
1). One of the most surprising aspects of
these results was the apparent discrepancy in the number of early lytic
and latent antigen-specific T cells detected by tetramer staining and
its relationship to clinical symptoms. Tetramer staining showed that
the proportion of CD8+ T cells specific for both a lytic
and a latent antigen was 2- to 3-fold higher during the acute phase in
patient 2 compared to patient 1. Although the overall number of
antigen-specific T cells dropped significantly as this patient
recovered from acute IM, the number of tetramer-positive, early lytic
antigen-specific T cells was still maintained at much higher levels
when compared to the rapidly recovered patient 1.
Significant phenotypic heterogeneity within antigen-specific T-cell populations was observed between the 2 patients, perhaps reflecting differences in the clinical symptoms and the duration of antigen exposure. A very high proportion (80%-100%) of both lytic and latent antigen-specific T cells from patient 1 during the acute phase of infection had an activated/memory phenotype with high levels of expression of CD38, CD44, and CD27. On the other hand, a much lower proportion (~60%) of antigen-specific T cells in patient 2 were positive for CD27. Similar heterogeneity in the expression of CD62L on antigen-specific T cells was observed during the acute phase. As the symptoms of acute infection resolved in both patients, the majority of antigen-specific T cells differentiated as effector/memory T cells (CD27- and CD62L-negative phenotype). Surprisingly, both acute IM patients continued to maintain a high proportion of T cells with an activated phenotype (CD38 positive) even after the resolution of acute infection, indicating continuing exposure to the viral antigens either in the lymph nodes or at other sites where the virus establishes its long-term latent infection. This study is the first to demonstrate directly that a broadly directed CTL response with strong functional activity was coincident with the resolution of acute EBV infection. This conclusion is strongly supported by previous studies on animal models of hepatitis C virus and lymphocytic choriomeningitis virus infection, which have shown that the breadth of the CTL response may be important in maintaining viral control.6-8 Overall the present study provides an important platform for future investigations on a larger cohort of patients, particularly those undergoing chronic active EBV infection, to determine if a narrowly focused T-cell repertoire with limited functional activity contributes to the protracted illness.
Mandvi Bharadwaj, Scott R. Burrows, Jacqueline M. Burrows, Denis J. Moss, Michelle Catalina, and Rajiv Khanna
References 1. Rickinson AB, Kieff E. Epstein-Barr virus. In: Fields BN,Knipe DM,Howley PM, eds. Fields Virology. Philadelphia, PA: Lippincott-Raven; 1996:2397-2446. 2. Khanna R, Burrows SR. Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. Annu Rev Microbiol. 2000;54:19-48[CrossRef][Medline] [Order article via Infotrieve]. 3. Steven NM. Epstein-Barr virus latent infection in vivo. Rev Med Virol. 1997;7:97-106[CrossRef][Medline] [Order article via Infotrieve]. 4. Bharadwaj M, Parsons PG, Moss DJ. Cost-efficient quantification of enzyme-linked immunospot. Biotechniques. 2001;30:36-38[Medline] [Order article via Infotrieve].
5.
Limaye AP, Huang ML, Atienza EE, Ferrenberg JM, Corey L.
Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders.
J Clin Microbiol.
1999;37:1113-1116
6.
Lechner F, Wong DK, Dunbar PR, et al.
Analysis of successful immune responses in persons infected with hepatitis C virus.
J Exp Med.
2000;191:1499-1512 7. Cooper S, Erickson AL, Adams EJ, et al. Analysis of a successful immune response against hepatitis C virus. Immunity. 1999;10:439-449[CrossRef][Medline] [Order article via Infotrieve].
8.
Moskophidis D, Battegay M, van den Broek M, Laine E, Hoffmann-Rohrer U, Zinkernagel RM.
Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus.
J Gen Virol.
1995;76:381-391   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
patient 1's acute phase was relatively brief (2-3 weeks),
and patient 2 sustained protracted symptoms (4 months). We have also
included a panel of HLA-matched, unrelated healthy virus carriers,
which allowed us to compare their CTL responses to the responses seen in the 2 acute IM patients. Although expansions of antigen-specific T
cells were observed in both patients during the acute phase of
infection, ex vivo analysis based on the enzyme-linked immunospot (ELISPOT) assay indicated that rapid recovery from IM symptoms in
patient 1 was clearly coincident with broad T-cell reactivity to
multiple epitopes within lytic and latent antigens and that protracted
illness in patient 2 correlated with a narrowly focused response
(Figure 
response was measured in ELISPOT assays as described
previously.
