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J Virol. May 2007; 81(9): 4904–4908.
Published online Feb 28, 2007. doi:  10.1128/JVI.02509-06
PMCID: PMC1900166

Lytic and Latent Antigens of the Human Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Induce T-Cell Responses with Similar Functional Properties and Memory Phenotypes[down-pointing small open triangle]

Abstract

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), multicentric Castleman's disease, and primary effusion lymphoma (2). Although KSHV-specific cellular immunity seems to play an important role in the control of this gammaherpesvirus (γ-herpesvirus), the kinetics, the antigen specificity, and the persistence of these responses have not been well documented nor have they been compared to cellular immune responses against other human γ-herpesviruses (30). Additionally, while CD8 T-cell responses induced by infection with other viruses such as Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) have been shown to produce an array of different cytokines and activation markers besides gamma interferon (IFN-γ) (4, 20), comparable data for the KSHV-specific cellular immunity are limited (19). In light of the recent findings demonstrating a beneficial role for polyfunctional T-cell responses in the control of HIV infection and the frequent comparisons made between HIV- and herpesvirus-specific immunity, it is important to determine whether KSHV-specific T-cell responses show similar levels of polyfunctionality and whether these responses reflect the maturation and functional characteristics described for responses targeting another human γ-herpesvirus, EBV. To address some of these issues, the present study was designed to initially identify dominant lytic and latent KSHV antigens and then to assess different T-cell functions, including the release of IFN-γ and tumor necrosis factor alpha (TNF-α), as well as the cell's ability to degranulate (CD107a expression) after antigen contact. These analyses included lytic and latent EBV-derived antigens for which phenotypic and functional patterns were determined and compared to those of KSHV-specific T-cell responses.

To assess dominance patterns of the KSHV-specific immune response, samples from 31 HIV-1-infected subjects with positive KSHV serology were screened for KSHV- and EBV-specific immunity, using an IFN-γ-based enzyme-linked immunospot (ELISPOT) assay as previously described (6). Assays were performed using synthetic overlapping peptides (OLP) spanning the KSHV-encoded lytic viral proteins Orf65 (a tegument protein) and Orf57 (MTA; 21 and 41 peptides, respectively), as well as the latent proteins Orf73 (LANA), K10.5 (LANA-2), and K12 (kaposin) (85, 76, and 51 peptides, respectively). The selection of antigens thus included viral open reading frames (ORFs) with well-established latent gene expression and lytic antigens against which humoral immune responses have been shown. Additionally, 92 EBV-derived cytotoxic T-lymphocyte (CTL) epitopes (30 epitopes from lytic and 62 epitopes from latent EBV proteins) were included (6, 7, 15). Humoral responses and cellular viral loads for KSHV and EBV were determined for 11 of these individuals as previously described (23, 31). With the exception of positive associations between CD4 T-cell counts and KSHV K8.1 antibody titer (P = 0.032) and a negative association between CD4 counts and EBV viral loads (P = 0.001), no statistically significant associations between clinical status and humoral or cellular immune responses were identified (data not shown).

Positive KSHV-specific ELISPOT responses to at least one KSHV antigen were detected in 18 out of the 31 (58%) subjects tested, compared to 24 patients who responded to EBV (77%). With the exception of the protein Orf65, all KSHV proteins tested were recognized in at least one patient, with 13 individuals (42%) targeting Orf57, followed by 29% targeting Orf73, 23% targeting K10.5, and 16% targeting K12. While these results confirmed the frequent recognition of Orf73-derived peptides seen in earlier analyses (32), no previous report has documented T-cell activities in response to Orf57, which the present data identify as a novel and frequent target of KSHV-specific cellular immunity. Of note, Orf57 was targeted not only as frequently as Orf73 but also with similar strength, as the median magnitude of responses to Orf57 (80 spot-forming cells [SFC]/106 peripheral blood mononuclear cells [PBMC]; range, 30 to 1,160 SFC) was comparable to that of responses against Orf73 (100 SFC/106 PBMC; range, 38 to 535 SFC; P > 0.05). Overall, however, despite their frequent recognition and magnitudes exceeding 1,000 SFC/106 PBMC in some individuals, KSHV-specific responses were generally weaker than responses to EBV-derived peptides (P = 0.0012) (Fig. (Fig.1).1). Although this reduced magnitude of responses may be due to the limited set of KSHV-specific antigens used and to the testing of specific immune responses using 18-mer overlapping peptides instead of optimally defined CTL epitopes, these data are in line with earlier studies that have found relatively weak KSHV-specific T-cell activity (10, 16, 32).

FIG. 1.
EBV-specific T-cell activity exceeds responses to KSHV antigens. KSHV- and EBV-specific T cells were assessed by IFN-γ ELISPOT assay using peptide pools containing overlapping peptides spanning lytic and latent KSHV antigen sequences or previously ...

To address whether the responses observed with the ELISPOT assays were mediated by CD8 or CD4 T cells and to define the immune phenotypes of these cells, responses to the two most frequently targeted lytic (Orf57) and latent (Orf73) KSHV antigens were further characterized by intracellular cytokine staining of cells from 11 subjects. Responses against Orf73 tended to be of greater magnitude (median of 0.20% specific cells; range, 0.16 to 0.37%) than those against Orf57 (median, 0.06%; range, 0.04 to 0.23%). Responses were mostly CD8 T-cell mediated, as only two samples showed borderline CD4 T-cell reactivity (data not shown). Analysis of the responses in the individual with the strongest Orf57-specific reactivity identified a novel HLA-B57-restricted epitope (Fig. (Fig.2A,2A, sequence ISARGQELF). Interestingly, a second subject, expressing HLA-B58, also showed consistent responses to Orf57. In line with previous data for epitope sharing among alleles of the HLA-B58 supertype (14), this individual was indeed found to target the same optimal IF9 epitope (Fig. (Fig.2B).2B). Subsequent HLA restriction analyses using cells from the HLA-B58-expressing subject and single-HLA class I-allele-expressing .221 cells showed specific recognition of the IF9 epitope in the context of HLA-B57 as well as of HLA-B58 (Fig. (Fig.2C).2C). Among the 18 subjects for whom HLA typing was available, a third individual expressed HLA-B58 yet did not mount this epitope-specific response. Together, the data identify both the Orf57 protein as a potent target of CD8 T-cell-mediated cellular immunity against KSHV and the first optimally defined Orf57-derived CTL epitope restricted by HLA-B57 and HLA-B58, two alleles associated with slow HIV-1 disease progression (24). Given the observation that some alleles associated with slow HIV disease progression have also been correlated with a better prognosis or even viral clearance in other viral infections (e.g., HLA-B27 and HLA-B57 in hepatitis C virus [22, 29]), the identification of KSHV-derived epitopes presented on these alleles may help to further characterize molecular mechanisms mediating these potentially beneficial effects. However, the small number of HLA-B57/B58-expressing individuals in the cohort tested did not permit us to assess whether KSHV viral loads would be significantly lower in these subjects.

FIG. 2.
Mapping and HLA restriction analyses of an optimal CTL epitope in Orf57. Recognition of the optimal IF9 epitope, defined as the peptide truncation eliciting the strongest responses at the lowest concentration, is shown in a cell line from an HLA-B57-expressing ...

Recent data by Betts et al. have shown that functional response patterns of HIV-specific CD8 T cells can vary drastically and that the presence of polyfunctional CTL populations is associated with better disease outcome (4). To investigate the polyfunctionality and maturation phenotypes of CD8 T cells targeting lytic or latently expressed KSHV antigens and to assess whether they share phenotypic and functional characteristics with cells targeting EBV-derived antigens, the ability of these cells to degranulate (as measured by the surface expression of CD107a [3]) and to secrete IFN-γ and TNF-α upon antigen stimulation was determined by flow cytometry. Given their frequent recognition and overall higher magnitudes, responses to the lytic Orf57 and latent Orf73 proteins were studied and contrasted to responses to lytic or latent EBV antigen-derived CTL epitopes. Positive responses were analyzed individually and stratified by virus and by lytic or latent antigen specificity. The data demonstrate that the median fraction of cells showing all three effector functions tested (IFN-γ+ TNF-α+ CD107a+) was almost 10-fold lower among cells targeting the lytic KSHV antigen Orf57 (5.4%) than among CD8 T cells responding to the latent antigen of Orf73 (47%; P = 0.031) (Fig. (Fig.3).3). Similarly, when CD8 T-cell responses to EBV-derived antigens were assessed, a significantly smaller fraction of CD8 T cells responding to lytic viral antigens was found to be triple positive (IFN-γ+ TNF-α+ CD107a+) than that targeting latent viral antigens (P = 0.005) (Fig. (Fig.33).

FIG. 3.
Functional analysis of IFN-γ-producing CD8 T cells. CD107a expression and TNF-α release were assessed for individual responses detected in 17 samples from 11 individuals after stimulation with peptide pools derived from lytic or latent ...

To assess whether antigen specificity would also translate into differences in T-cell maturation markers, the immune phenotypes of responses to lytic and latent γ-herpesvirus antigens were compared (9, 12). Indeed, when responses to lytic and/or latent antigens from both viruses were analyzed separately, a significant difference in the differentiation markers on lytic or latent antigen-specific CD8 T cells was observed (Fig. (Fig.4).4). In particular, effector-memory T cells (CCR7 CD45RA) were more frequently detected in T-cell populations responding to latently expressed antigens than in T cells targeting lytic antigens (P = 0.015 for KSHV; P = 0.019 for EBV). Together, the data substantiate previous reports that have identified an antigen-specific phenotypical and functional dichotomy between EBV-specific CD8 T-cell responses recognizing either lytic or latent CTL epitopes (8, 11, 17, 18). The data also demonstrate that the CD8 T-cell immunity against these two human γ-herpesviruses show close parallels in the functional and maturation phenotype for responses targeting lytic and latent viral antigens.

FIG. 4.
Phenotypic analysis of IFN-γ-producing CD8 T cells. The expression of the effector-memory or the effector cell phenotype was compared between individual T-cell responses shown in Fig. Fig.3.3. Cells responding to either KSHV (left panel) ...

A number of studies have suggested that KSHV-specific immune responses are generally of low magnitude, especially compared to that of EBV- or HIV-specific immunity (16, 26, 32). However, the present data, based partly on KSHV-encoded antigens previously not assessed, indicate that some individuals can mount responses that equal their EBV-specific reactivity. Although methodological differences (testing overlapping peptides versus optimal epitopes) may contribute to the reduced strength of these responses, the data indicate that future analyses of the overall magnitude of KSHV-specific responses will need to be revisited using more extensive viral antigen test sets. Although technically demanding and cost intensive, this would ideally be based on studies similar to analyses performed for cytomegalovirus (CMV), where responses to the entire viral proteome were measured using a comprehensive set of overlapping peptides (28). Furthermore, EBV-specific immune responses are generally assessed using optimally defined CTL epitopes. These may select for particularly frequent and strong responses that in in vitro analyses do not require extensive processing for the efficient detection of responses. In addition, optimal epitopes may elicit broader effector functions at lower concentrations than overlapping peptides, potentially influencing the detectable functionality patterns of these cells (5). Thus, the OLP approach used for measuring KSHV-specific responses may underestimate the magnitude of KSHV-specific T-cell responses, and direct comparisons of additional gene products using matching peptide test sets will be required.

In this regard, identification of the Orf57 protein as a frequent and potent lytic immune target may provide a valuable candidate for future analyses and may help reveal mechanisms that contribute to its frequent recognition. In particular, the evolutionarily well-conserved amino acid sequence of Orf57 makes it unlikely that responses may be missed due to differences between the peptide test set and the protein sequence in the infecting virus (1, 15, 21, 27). The early expression of Orf57 in the lytic viral life cycle may also partly explain its frequent targeting by T cells and may reveal potential parallels in immunodominance patterns with EBV-specific responses, where the focus of CTL activity is on immediate-early and early viral targets. This focus of the EBV-specific CTL response is presumably due to the effective presentation of early and immediate-early antigen-derived epitopes before the immune regulatory effects mediated by antigens expressed later may interfere with antigen processing and presentation (25). While broader immune analyses, analyzing responses to multiple immediate-early and early KSHV proteins, will be needed, the present findings point to possible shared mechanisms in the generation of hierarchy profiles of the γ-herpesvirus-specific cellular immunity.

Together, the present report is the first study that directly compares cellular immune responses to lytic and latent cycle antigens of two closely related human γ-herpesviruses and, given previous comparisons between EBV- and CMV-encoded antigens, identifies surprisingly close parallels between the immune phenotypes of cells specific for these pathogens (9, 12, 19, 33). This also implies that previously noted differences in the expression of maturation and activation markers on EBV- and CMV-specific CTLs may be due to the comparison of two herpesviruses belonging to different subfamilies and that care must be taken when comparing “defective” HIV-specific immune responses to herpesvirus-specific immunity (9, 13, 33).

Acknowledgments

This work was supported by NIH/NIDCR program grant PO1 DE01438-01 and NIH HMS CFAR (P30 AI060354). F.B. was supported by the Swiss National Science Foundation, Switzerland (SNF-PBSKB-102686). E.E.B. and T.M.W. were supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the National Cancer Institute Research Contract N01-CP-21121.

We thank the Harvard Center for AIDS Research for funding the flow cytometry instrument (LSRII) used in these studies.

Footnotes

[down-pointing small open triangle]Published ahead of print on 28 February 2007.

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