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Cell-Mediated Immunity to Varicella-Zoster Virus Ann M. Arvin

Departments of Pediatrics and of Immunology and Microbiology, Stanford University School ofMedicine, Stanford, California

Natural varicella-zostervirus (VZV) infection and immunization with liveattenuated varicella vaccine elicits T lymphocytes that recognize VZV glycoproteins, gpI-V, and the immediate earlyjtegument protein, the product of gene 62 (IE62). Proliferation or cytotoxicityassays, done under limiting dilution conditions to estimate responder cell frequencies, indicate no preferential recognition of VZV proteins by human T cells. Analysis of the primary cytotoxic T lymphocyte (CTL) response after vaccination demonstrates that both gpI and IE62 are targets of the early response. CD4+- and CD8+-mediated CTL recognition of these viral proteins can be detected with natural and vaccine-induced immunity. Responder cell frequencies for protein-specific T cell proliferation and CTL function are generally comparable in subjects with natural and vaccine-acquired immunity to VZV. Exogenous reexposure to VZV results in enhanced T cell proliferation and may be an important mechanism for maintaining virus-specific cellular immunity. Providing exogenous reexposure by givingvaricellavaccine to individualswho have preexisting natural immunity markedly increases the responder cell frequencies ofT cells that proliferate in response to VZV antigen and the numbers of circulating CTL that recognize VZV proteins.

The introduction of immunosuppressive regimens for cancer therapy and for preventing transplant rejection was accompanied by observations that these regimens predispose patients to severe varicella and to a high incidence of herpes zoster caused by reactivation of varicella-zoster virus (VZV). The relationship between this clinical experience in immunodeficient patients and the suppression of their cell-mediated immune responses to VZV was first demonstrated using the in vitro proliferation assay [1-3]. In this assay, peripheral blood mononuclear cells (PBMC) are incubated 5-7 days with extract made from virus-infected cells or with an uninfected cell control; antigen-specific T cell stimulation is detected by measuring 3[H]thymidine incorporation. Proliferation is expressed as the stimulation index, the ratio of counts per minute between antigen-stimulated and control wells. Antigen-stimulated proliferation is accompanied by the production of lymphokines, such as interleukin-2 and ')'-interferon, by T lymphocytes from immune subjects. T cells that exhibit cytotoxic activity (CTL) against target cells expressing VZV antigens can also be demonstrated by secondary in vitro exposure of PBMC from immune individuals to VZV antigen.

Received 31 December 1991; revised 23 March 1992. For studies done at Stanford University, informed consent was obtained according to US Department of Health and Human Services and Stanford University guidelines for research involving human subjects. Financial support: National Institutes of Health (AI-20459, -18449); Merck. Reprints or correspondence: Dr. Ann M. Arvin. Department of Pediatrics, Stanford University Medical Center, Stanford, CA 94305-5119.

The Journal of Infectious Diseases 1992;166(Suppll):S35-41 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6651-0006$01.00

Clinical Correlations with VZV T Lymphocyte Proliferation The VZV T cell proliferation assay has been used to establish correlations between the presence or absence of virusspecific cell-mediated immunity and the occurrence or outcome of clinical disease caused by the virus (table 1). For example, healthy children who have detectable T cell proliferation immediately after the appearance of the varicella exanthem have mild primary VZV infection. Immunodeficient children who fail to acquire VZV-specific T cell proliferation are subject to progressive disseminated varicella [4]. Intact cellular immunity appears to be an important component of the host response in stopping the viremic phase of infection and limiting viral replication at localized cutaneous sites during primary VZV infection. Elderly adults who are otherwise healthy and patients receiving immunosuppressive therapy have diminished VZV T cell proliferation responses and are more likely to reactivate VZV, resulting in herpes zoster [2, 3, 5,6]. Among high-risk populations, low or absent cellular immune responses seem to be necessary, but not sufficient alone, for occurrence of clinically symptomatic recurrent VZV [3]. When VZV-specific cell-mediated immunity is undetectable, viral reactivation in the immunocompromised host can produce disseminated disease, which resembles primary infection. Bone marrow transplant recipients are at particular risk for fatal progressive VZV following reactivation of latent virus [7]. The VZV T cell proliferation assay can also be done under limiting dilution conditions by incubating serial dilutions of PBMC with VZV antigen in multiple replicates. This method yields an estimate of the number of circulating T lymphocytes that recognize VZV antigens, which is referred to as the

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Table 1. Correlations between cell-mediated immunity and VZV disease.

Host Healthy Susceptible Immune Immune Immunodeficient Susceptible Immune

Clinical finding

VZV Tcell proliferation

Varicella Varicella exposure Age >65 years

Early acquisition Enhanced response Low or absent response

Mild infection No disease

Varicella

Delayed or no acquisition Low or absent response

Risk of dissemination Risk of herpes zoster and dissemination

Correlation

Risk of herpes zoster

responder cell frequency. After their induction during varicella, VZV-specific memory T lymphocytes are maintained at precursor frequencies of '" 1:40,000 PBMC in immune adults [8, 9]. While the responder cell frequency assay measures proliferation of the same T cell population as the standard T cell proliferation method, the use of multiple replicates reduces the assay-to-assay variability and may allow the detection of more subtle differences in the host response than the stimulation index. The age-related increase in the risk of herpes zoster among otherwise healthy elderly subjects has been correlated with waning cellular immunity, which can be shown to reflect a decrease in VZV-specific responder cell frequencies [10]. When VZV reactivation occurs in older individuals, the number ofcirculating VZV-specific T cells increases as a consequence of the reexposure to VZV in vivo; VZV responder cell frequencies are restored to numbers equivalent to those measured in younger immune subjects [10]. More recently, the proliferation assay has been used to demonstrate that the aka/Merck live attenuated varicella vaccine (Merck, West Point, PA) elicits VZV-specific cellular immunity [11-14]. That the live attenuated varicella vaccine induces cellular as well as humoral immunity to VZV is likely to be an important factor underlying the excellent protective efficacy of the vaccine observed in clinical studies of children and adults. Of healthy children given the varicella vaccine, 98%-100% have T cell recognition ofVZV antigens by 2-6 weeks after immunization, as would be expected among healthy children who were convalescent from natural varicella [4, 11, 13]. By using the responder cell frequency assay to analyze T cell proliferation, healthy adult vaccinees, who were immunized a mean of 3.5 years before evaluation, had frequencies of 1:18,000 ± 2000 SE compared to 1:39,000 ± 3000 SE in naturally immune adults who had varicella in childhood (P = .001, t test for 2 means) [IS].

110 1992;166 (Suppl I)

This finding of higher VZV-specific responder cell frequencies in the vaccinees is likely to be due to the shorter interval from primary exposure of the host to VZV antigens and allows for the possibility that significant numbers of responder cells will persist even if a gradual decline occurs during subsequent years after immunization. Cell-mediated immunity is elicited less reliably in leukemic children given the varicella vaccine, consistent with the finding that immunocompromised children often have diminished T cell proliferation to VZV antigens following natural varicella [I, 4, 12]. The evaluation of the varicella vaccine in children with leukemia also provides further evidence ofthe importance ofcellular immunity in reducing the risk of VZV reactivation. VZV-specific T cell proliferation was lower in 4 children who developed herpes zoster than in 29 vaccinated subjects who did not experience recurrent VZV [16].

Viral Protein Specificity of VZV T Cell Proliferation Response The development of methods to prepare subunit antigens has enabled identification of some of the viral proteins that are recognized by VZV-specific T cells in the in vitro proliferation assay (table 2). The initial investigation of the protein specificity of VZV T cell proliferation showed that T lymphocytes from healthy immune subjects recognized immunoaffinity-purified VZV glycoproteins, gpl and gplll, and pi 70 [17]. gpl and gplll are membrane proteins that are made abundantly in tissue culture cells infected in vitro and, more importantly from the perspective of the host response, their synthesis has been demonstrated within cells from lesions caused by primary or recurrent VZV infection in vivo [18]. The pi 70 is now identified as the product of the immediate early gene (IE62) of VZV and is homologous to the herpes simplex virus ICP-4 gene product. The IE62 protein is an

Table 2. VZV proteins and peptides recognized by T lymphocytes from immune individuals. Assay

T cell subset

T cell proliferation Proteins Peptides T cell cytotoxicity Induction of clonal expansion by secondary stimulation Recognition of target cells expressing VZV proteins

NOTE.

Viral proteins

gpl, gpII, gpIII, gpIV, IE62 gpl, gpII, gpIV. IE62

gpl, gpII, gpIV gpl, gpIV. gpV, IE62 gpl, gplv, gpV, IE62

gp, glycoprotein; IE, immediate early.

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Cell-Mediated Immunity to Varicella-Zoster Virus

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Figure 1. Responder cell frequencies of T lymphocytes specific for VZV whole antigen, immediate early protein (lE62), and glycoprotein (gpI) in healthy adults with vaccine-induced or natural immunity to VZV determined by limiting dilution proliferation assay. VZV-specific responder cell frequencies ± SE (vertical axis) to whole VZV antigen, IE62, and gpI are shown in relation to source of immunity: naturally acquired (NI; shaded bars) induced by immunization with varicella vaccine (vacc; open bars). n = 5 tested in each group. (Reprinted with permission from (15).)

interesting target of the host response because it has regulatory function and is also a major component of the virion tegument [19]. T lymphocytes that recognize gpl, gpIlI, and the IE62 protein are elicited during primary VZV infection although the kinetics of acquisition of T cell immunity to each of these VZV proteins varies in the normal host [17]. In addition, natural infection with VZV induces T cells that recognize gpll and gpV [20, 21]. As measured by T cell proliferation and lymphokine production, cell-mediated immunity to IE62 protein and to the glycoproteins, gpl, -II, -III, and -V, persists for years after primary VZV infection in the immunocompetent host [17, 20, 21]. Immunization with current preparations of the varicella vaccine elicits T lymphocytes that proliferate and produce lymphokines in response to stimulation with IE62 protein and the viral glycoproteins, generating responses that are comparable to those of subjects with naturally acquired immunity to VZV [13, 14]. When immunoaffinity-purified VZV proteins were used to stimulate T cells in the responder cell frequency assay, the number of circulating T lymphocytes that recognized gpl was equivalent among healthy adult recipients ofvaricella vaccine and adults with naturally acquired immunity to VZV (figure 1) [15]. The mean responder cell frequency for T lymphocytes recognizing IE62 protein was 1:135,000 ± 19,000 SE in naturally immune subjects and 1:230,000 ± 50,000 SE in those with vaccine immunity, but the difference was not statistically significant (P = .07, t test for 2 means). In these experiments, naturally

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immune subjects had significantly more T lymphocytes that proliferated in response to IE62 protein than to gpl (P = .01, paired t test). The protein specificityofcellular immunity to VZV can be further analyzed by stimulating T cells with synthetic peptides that reproduce short amino acid sequences present in the intact protein (table 2). In contrast to antibody-binding epitopes that are often dependent upon maintaining the conformation of the native protein, T cell epitopes typically correspond to a linear sequence of r - 8-12 residues and therefore can be mimicked by synthetic peptides. In initial experiments, VZV immune subjects were shown to have T cells that recognized predicted amphipathic peptides ofVZV gpll and IV [22]. Synthetic peptides corresponding to 10 nonoverlapping regions of the IE62 protein and ofgpl have also been tested in a large scale proliferation assay in which multiple wells were stimulated with each peptide to provide enough replicates for statistical analysis of T cell responses [23]. These experiments showed that several linear amino acid sequences of the IE62 protein were recognized by peripheral blood T lymphocytes from VZV immune donors. A combination of two IE62 peptides provided epitopes recognizable by T cells from each of 12 VZV immune donors. One gpl peptide, in combination with either oftwo other gpl peptides, induced proliferation of T cells from all immune subjects. These observations indicate that VZV infection elicits a diverse cell-mediated immune response in the natural host that is not restricted to one or two regions of particular VZV proteins.

CTL Response Elicited by Natural VZV Infection Although the classic antiviral CTL response has been considered to be mediated by CD8+ T lymphocytes that recognize viral proteins in the context of the class I major histocompatibility complex (MHC), CD4+ class II-restricted T cells have been identified most readily as having cytotoxic function against VZV-infected targets. CD4 + CTL derived by secondary in vitro stimulation ofPBMC have been shown to lyse VZV-infected autologous lymphoblastoid cells [24, 25]. However, CD8+-mediated CTL activity has also been demonstrated against VZV-infected fibroblasts, targets that express only the class I MHC antigen, and by testing purified CD8+ T cells as effectors against lymphoblastoid cells expressing VZV proteins [26, 27]. A number of questions arise about the CTL component of cell-mediated immunity to VZV. Do the viral proteins that elicit T cell proliferation also serve as targets for VZV-specifie CTL? Is the VZV CTL response selective for specific viral proteins? Are internal or regulatory proteins, such as IE62, recognized preferentially by CTL compared to membraneexpressed viral glycoproteins? For example, immediate early proteins of cytomegalovirus have been identified as impor-

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tant targets of antiviral cytotoxicity, whereas the glycoproteins Band D of herpes simplex virus are recognized effectively by CTL [28, 29]. Finally, to assess some of the potential contribution ofCD4+ and CD8+ CTL, it is ofinterest to determine the frequencies of memory CTL that recognize VZV proteins within these T cell subpopulations. Some of these questions have been addressed in recent experiments using VZV-vaccinia recombinants to generate targets expressing a single VZV protein [27]. Limiting dilution conditions were used for the cytotoxicity assay so that frequencies ofVZV-specific CTL could be determined. Cytotoxicity experiments usedClf-l" and CD8+ T lymphocytes, separated to >99% purity by flow cytornetry, as effector cells. Superinfection of autologous lymphoblastoid cells with VZV-vaccinia recombinants provided targets with the potential to express the VZV proteins in natural association with either the class I or class II MHC molecule. In these experiments, the mean precursor frequency for T lymphocytes that recognized the IE62 protein was 1:105,000 ± 85,000 SD, compared to I: 121,000 ± 86,000 SD for gpI. CTL that recognized the IE62 protein or gpl were generated from CD4+ and CD8+ populations, and the precursor frequencies of CTL specific for the IE62 protein and gpl were equivalent within the CD4+ and CD8+ subpopulations (figure 2). More recently, this approach has been used to demonstrate lysis of targets expressing gplV and gpV by effector cells derived from PBMC of VZV immune donors [15]. The mean frequency of CTL specific for gplV was 1:170,000 ± 71,000 SE, and that for gpVwas I: 108,000 ± 27,000 SE in naturally immune subjects. In addition to these experiments with short-term CTL cultures, VZV-specific CD4+ T cell clones that recognize gplIV, have been generated [30, 31]. Of note, some of these clones were shown to express helper function for production ofantibodies by B lymphocytes and CTL activity. Cytotoxicity against VZV targets is also observed using immunoaffinity-purified gpl to generate CTL from immune subjects in long-term T cell cultures [25].

Kinetics and Protein Specificity of CTL Response Elicited by Varicella Vaccine To evaluate vaccine-induced cellular immunity, it is important to determine whether immunization with the varicella vaccine induces memory CTL that recognize VZV and to compare CTL responses after vaccination with those elicited by natural VZV infection. When the kinetics of the initial CTL response was analyzed, the mean frequency ofCTL specific for IE62 protein was I: 171,000 ± 46,000 SE in 10 subjects tested 10 days-8 weeks after the first dose of varicella vaccine [15]. The initial induction of the gpl-specific cytotoxic response was equivalent to the response to IE62 protein with a mean frequency of 1:166,000 ± 49,000 SE

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1:250,000

1:150,000

1:50,000

CD4

COB

IE PROTEIN

CD4

COB

gpl PROTEIN

Figure 2. Precursor frequencies of cytotoxic T lymphocytes (CTL) specific for immediate early protein (IE62) and glycoprotein (gpI) ofVZV within CD4+ and CD8+ T lymphocyte populations. T lymphocytes were separated from peripheral blood by fluorescence-activated cell sorter under sterile conditions and incubated with inactivated VZV antigen in limiting dilution cultures; initial T cell concentrations ranged from 0, I X 103,2 X 103, I X 104 , 5 X 104 , and I X 105 • After 12 days, effector cells were tested for Iysisof autologous lymphoblastoid cell lines infected with vaccinia virus recombinant that expressed VZV IE62· or gpI or with a vaccinia control recombinant. Precursor frequency estimates were derived by statistical analysis of standard limiting dilution plots. T lymphocytes from I donor were tested for CTL activity against IE62 only; cells from 2 donors were tested with gpI target only. T cell subpopulations from 4 donors were evaluated against VZV IE62 or gpI targets in parallel; connected points indicate precursor CTL frequencies from these assays. (Reprinted with permission from [27).)

CTL (figure 3). Cultures of T lymphocyte subpopulations obtained within 12 weeks after immunization showed that lysis of targets expressing VZV proteins could be mediated by either CD4+ or CD8+ T lymphocytes (table 3). When the persistence of CTL responses to IE62 protein, gplV and gpV were examined in vaccinees tested --4 years after immunization, the mean CTL frequencies specific for IE62 protein (1: 131,000 ± 40,000 SE) and for gplV (1: 155,000 ± 60,000 SE) were comparable in vaccinees and in adults with natural immunity. Although the mean frequency ofCTL specific for gpV was lower in these vaccinees (1 :208,000 ± 53,000 SE) than in naturally immune subjects, the difference was not statistically significant (P = .15).

Role of Exogenous Reexposure to VZV in Maintaining T Cell Immunity to VZV The mechanism by which cellular immunity to VZV is maintained after primary infection in childhood is an important issue that has implications for vaccine development. One hypothesis is that cellular immunity may be enhanced

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Cell-Mediated Immunity to Varicella-Zoster Virus

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Figure 3. Kinetics of acquisition of cytotoxic T lymphocytes (CTL) specific for VZV immediate early protein (lE62) and glycoprotein (gpI) after immunization with varicellavaccine. VZV-specificCTL frequency estimates (vertical axis) are shown for individuals tested after one dose of vaccine at intervals shown on horizontal axis. CTL frequencies for 10 susceptiblevaccine recipients (e); data for 2 vaccinees with preexisting naturally acquired VZV immunity (0); for 2 subjects with recent acute varicella (A). Connected points indicate CTL frequencies for IE62 and gpl targets determined in same subject. (Reprinted with permission from [I 5].)

periodically because of the annual epidemics of varicella. The increase in VZV T cell proliferation observed in immune adults after household contact with a child with varicella suggests a role for exogenous reexposure [32]. Immune children who are reexposed to varicella also have a significant enhancement of delayed hypersensitivity to VZV antigens demonstrated by skin testing [33]. Although symptomatic reinfection with VZV is rare, these immunologic changes indicate that reexposure to the virus may result in subclinical reinfection or a sufficient uptake of viral antigens by antigen-presenting cells at local sites of inoculation to boost cellular immunity. The availability of varicella vaccine has enabled direct assessment of the effects ofexogenous reexposure to VZV antigens upon virus-specific cell-mediated immune responses. Whether deliberate reexposure by immunization enhances cell-mediated immunity has clinical relevance because vaccination might be an approach to reduce the risk of herpes zoster associated with waning immunity [34]. In recent experiments, VZV-specific responder cell frequencies were increased from I :68,000 to I :40,000 in healthy adults >55 years old who received varicella vaccine and higher responder cell frequencies persisting ~2 years after immunization [35]. Increased production of ,,-interferon by PBMC incubated with VZV antigen was also documented in these vaccine recipients.

Although data about the potential of immunization to boost CTL responses are limited, the highest frequencies of CTL specific for VZV proteins were observed in 2 vaccine recipients who had preexisting naturally acquired VZV immunity (figure 3). The CTL frequencies were I :5000 for 1£62 protein and I :8000 for gpl in I immune subject evaluated 3 weeks after receiving the initial dose of varicella vaccine. A second immune subject, tested 8 weeks after immunization, had CTL frequencies of I: 14,000 for 1£62 protein and I :40,000 for gpl.

Role of Endogenous Reexposure to VZV in Maintaining T Cell Immunity to VZV Asymptomatic reactivations of latent virus are common after primary infection with other human herpesviruses. These episodes provide a mechanism for repeated stimulation ofcellular immune responses by endogenous reexposure to replicating virus. In contrast, it is difficult to determine whether in vivo restimulation is involved in maintaining VZV-specific cellular immunity because asymptomatic VZV reactivation is difficult to document. Unless herpes zoster lesions are present, it is not possible to prove VZV reactivation by recovery of infectious virus. Nevertheless, reactivation that does not progress to cutaneous lesions is theoretically possible in immune individuals because latent infection of dorsal root ganglia cells is a predictable consequence of primary VZV infection. Bone marrow transplant patients provide a special population in which to study whether subclinical VZV reactivation occurs and whether it plays a role in enhancing cellular immunity. Cell-mediated immunity to VZV is recovered by many bone marrow transplant recipients without any intervening clinical signs of herpes zoster [2]; therefore, if VZV reactivation is necessary to stimulate the recovery of virusspecific immunity, many patients must experience subclini-

Table 3. Detection of cytotoxicT lymphocytes(CTL) specific for immediate early protein (lE62) or glycoprotein (gpl) in cultures of purified CD4+ and CD8+ T lymphocyte subpopulations after immunization with live attenuated varicella vaccine. CD4+ CTL recognition Interval after immunization 10 days 16 days 8 weeks 12 weeks 12 weeks NOTE.

CD8+ CTL recognition

IE62

gpI

IE62

gpl

+ 0 0 0

0 0 0

+ +

0 0

0

+

+

+

0

+

+

0

+

+, positive; O. not found.

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cal episodes of viral replication. However, technical problems with documenting asymptomatic VZV reactivation have interfered with the investigation of this aspect of VZV pathogenesis. In a recent study, PBMC from bone marrow transplant patients were tested for the presence ofVZV DNA using the polymerase chain reaction method [36]. Subclinical cell-associated VZV viremia was documented in 19% of bone marrow transplant patients. Since most patients were tested only once after transplantation, the actual frequency of occult reactivation is probably higher. When documented episodes of subclinical VZV viremia were combined with those of symptomatic herpes zoster, 41% of VZV-seropositive bone marrow transplant recipients experienced VZV reactivation. None of 12 patients tested before VZV reactivation had T lymphocyte proliferation to VZV antigen. However, among patients tested > 100 days after transplant, 5 (63%) of 8 with detectable T cell proliferation had experienced subclinical or clinical VZV reactivation compared to none of 6 patients who lacked VZV T cell responses. These experiments suggest that in vivo reexposure to VZV antigens due to subclinical VZV viremia as well as to symptomatic VZV reactivation may account for the recovery of virus-specific T cell immunity after bone marrow transplantation. Generalizing from the observation ofsubclinical reactivation in this immunocompromised patient population to its occurrence in healthy individuals remains speculative. However, unless host or viral mechanisms for restricting the replication of latent VZV are extraordinarily efficient compared with those governing other herpesviruses, periodic subclinical reactivation in otherwise healthy subjects seems likely.

References I. Patel PA. Yoonessi S, O'Malley J, Freeman A, Gershon A, Ogra PL.

2.

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Cell-mediated immunity to varicella zoster virus infection in subjects with lymphoma or leukaemia. J Pediatr 1979;94:223-30. Meyers JD, Flournoy N, Thomas ED. Cell-mediated immunity to varicella-zoster virus after allogeneic marrow transplant. J Infect Dis 1980; 141:479-87. Arvin AM, Pollard RB. Rasmussen LE, Merigan TC. Cellular and humoral immunity in lymphoma patients. J Clin Invest 1980;65:86978. Arvin AM, Koropchak CM, Williams BRG, Grumet FC, Foung SK. Early immune response in healthy and immunocompromised subjects with primary varicella-zoster virus infection. J Infect Dis 1986; 154:422-9. Miller AE. Selective decline in cellular immune response to varicella zoster in the elderly. Neurology 1980;30:582-7. Berger R, Florent G, Just M. Decrease of the Iymphoproliferative response to varicella-zoster virus antigen in the aged. Infect Immun 1981;32:24-7. Locksley RM, Flournoy N, Sullivan KM, Meyers JD. Infection with varicella zoster virus after bone marrow transplantation. J Infect Dis 1985; 152: II 72-80.

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8. Hayward AR, Herberger M. Lymphocyte responses to varicella-zoster virus in the elderly. J Clin Immunol 1987;7: 174-8. 9. Diaz PS, Smith S, Hunter E, Arvin AM. Immunity to whole varicellazoster virus antigen and glycoproteins I and p 170: relation to the immunizing regimen oflive attenuated varicella vaccine. J Infect Dis 1988; 158: 1245-52. 10. Hayward A, Levin M. WolfW, Angelova G, Gilden D. Varicella-zoster virus-specific immunity after herpes zoster. J Infect Dis 1991;163: 873-5. II. Arbeter AM, Starr SE, Weibel RE, Plotkin SA. Varicella vaccine studies in healthy children and adults. Pediatrics 1986;78(suppl):74856. 12. Gershon AA, Steinberg SP, Gelb L, et al. Live attenuated varicella vaccine: efficacy for children with leukemia in remission. JAMA 1984;252:355-62. 13. Watson B, Keller PM, Ellis RW, Starr SE. Cell-mediated immune responses after immunization of healthy seronegative children with varicella vaccine: kinetics and specificity. J Infect Dis 1990; 162: 794-9. 14. Bergen RE. Diaz PS, Arvin AM. The immunogenicity of the Oka/ Merck varicella vaccine in relation to infectious varicella-zoster virus and relative viral antigen content. J Infect Dis 1990; 162: 1049-54. 15. Sharp M, Terada K, Wilson A, et al. Kinetics and viral protein specificity of the cytotoxic T lymphocyte response in healthy adults immunized with live attenuated varicella vaccine. J Infect Dis 1992; 165:852-8. 16. Hardy IB, Gershon AA, LaRussa PS, Steinberg SP. The incidence of zoster after immunization with live attenuated varicella vaccine: a study in children with leukemia. N Engl J Med 1991;325:1545-50. 17. Arvin AM, Kinney-Thomas E, Shriver K, et al. Immunity to varicellazoster viral glycoproteins, gpl (90/58) and gpIII (gp 118), and to a nonglycosylated protein, p 170. J Immunol 1986; 137: 1346-51. 18. Grose C. Immunology of varicella-zoster virus glycoproteins. J Infect Dis 1988; 157:877-81. 19. Kinchington PR, Houghland JK, Arvin AM, Ruyechan WT, Hay J. Varicella zoster virus IE62 protein is a major virion component. J Virol 1992;66:359-66. 20. Giller RH, Winistorfer S. Grose C. Cellular and humoral immunity to varicella zoster virus glycoproteins in immune and susceptible human subjects. J Infect Dis 1989;160:919-28. 21. Giller RH, Winistorfer S, Grose C. Cellular and humoral immunity to varicella-zoster virus (VZV) glycoprotein V (gpV): studies using a recombinant viral antigen [abstract 412]. Presented at the 15th International Herpesvirus Workshop, Washington, DC, 1990. 22. Hayward AR. T-cell responses to predicted amphipathic peptides of varicella-zoster virus glycoproteins II and IV. J Virol 1990;64:651-

5. 23. Bergen RE, Sharp M, Sanchez A, Judd AK, Arvin AM. Human T cells recognize multiple epitopes of an immediate early/tegument protein (IE62) and glycoprotein I of varicella-zoster virus. Viral Imrnunol 1991;4:151-66. 24. Hayward AR, Pontesilli 0, Herberger 0, Laszlo M. Levin M. Specific lysis of varicella zoster virus-infected B Iymphoblasts by human Tcells. J Virol 1986;58: 179-84. 25. Diaz PD, Smith S, Hunter E, Arvin AM. T-Iymphocyte cytotoxicity with natural varicella-zoster virus infection and after immunization with live attenuated varicella vaccine. J Immunol 1989; 142:636-41. 26. Hickling JK, Borysiewicz LK, Sissons JGP. Varicella-zoster virus specific cytotoxic T lymphocytes (Tc): detection and frequency analysis of HLA class I-restricted Tc in human peripheral blood. J Virol 1987;61 :3463-9. 27. Arvin AM, Sharp MS, Smith S, et al. Equivalent recognition ofa varicella-zoster virus immediate early protein (lE62) and glycoprotein I

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by cytotoxic T-Iymphocytes of either CD4+ or CD8+ phenotype. J ImmunoI1991;146:257-64. Zarling JM. Moran PA, Burke RL. Pachl C, Berman PW. Lasky LA. Human cytotoxic T cell clones directed against herpes simplex virusinfected cells. IV. Recognition and activation by cloned glycoproteins gB and gO. J Immunol 1986; 136:4669-73. Borysiewicz L. Morris S. Page J. Sissons J. Human cytomegalovirus specific cytotoxic T lymphocytes: requirements for in vitro generation and specificity. Eur J Immunol 1983; 18:269-75. Hayward A, Giller R. Levin M. Phenotype. cytotoxic. and helper functions of T cells from varicella zoster virus stimulated cultures of human lymphocytes. Viral. Immunol 1989;2: 175-84. Huang Z. Vafai A. Hayward AR. Specific lysis of targets expressing VZV gpI or gpIV by CD4+ clones. [abstract 413]. Presented at the 15th International Herpesvirus Workshop. Washington. DC, 1990.

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32. Arvin AM. Koropchak CM. Wittek AE. Immunologic evidence of reinfection with varicella-zoster virus. J Infect Dis 1983;148:200-5. 33. Kamiya H. Ihara T. Hattori A. et al. Diagnostic skin test reactions with varicella zoster virus antigen and clinical application of the test. J Infect Dis 1977; 136:784-8. 34. Berger R. Luescherm D. Just M. Enhancement of varicella zoster specific immune responses in the elderly by boosting with varicella vaccine. J Infect Dis 1984; 149:647-52. 35. Levin MJ. Murray M. Rotbart HA, Zerbe GO. White CJ. Hayward AR. Immune response of elderly individuals to a live attenuated varicella vaccine. J Infect Dis 1992;166:253-9. 36. Wilson A, Sharp M. Koropchak CM. Ting SF. Arvin AM. Subclinical varicella-zoster virus viremia. herpes zoster. and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 1992;165:119-26.

Cell-mediated immunity to varicella-zoster virus.

Natural varicella-zoster virus (VZV) infection and immunization with live attenuated varicella vaccine elicits T lymphocytes that recognize VZV glycop...
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