Virus: An Overview Ann M. Arvin Department of Pediatrics, Stanford University School of Medicine, Stanford, California
INNATE IMMUNITY appear to be effective for delaying the acquisition of
adaptive immunity; VZV-specific T cells were not de- Under conditions of naturally acquired primary vari-
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tected during the incubation period and emerged grad- cella-zoster virus (VZV) infection, the first response of ually after the onset of the varicella rash, appearing in the naive host is mediated by the innate immune system 12%, 31%, and 47% of healthy subjects with varicella through antiviral cytokines and the activation of NK who were tested at 1, 2, and 3 days after onset, re- cells [1]. These responses are likely to be important for spectively [7, 8]. Nevertheless, the acquisition of VZV- the initial control of VZV at mucosal sites of inocu- specific T cells appears to be necessary to prevent lation and to trigger the induction and amplification disseminated infection, as suggested by the risk of life- of adaptive, VZV-specific immunity. NK cells can lyse threatening varicella in children with malignancies or VZV-infected targets [2], and activated NK cells are a congenital T cell immunodeficiencies or who are re- major source of interferon (IFN)–g production, which ceiving immunosuppression for organ transplantation, enhances the clonal expansion of antigen-specific T as well as to achieve resolution of the acute infection. cells. IFN-a inhibits VZV replication in vitro, and treat- Children with HIV infection are at risk for chronic ment with exogenous type I IFN-a reduced the severity varicella, which is consistent with an important role for of varicella in immunocompromised children with var- VZV-specific cellular immunity [9]. High frequencies icella [3]. In addition, VZV replication in skin is as- of T cells that lyse targets expressing VZV gE and im- sociated with extensive production of IFN-a by adja- mediate early (IE) 62 protein are detected in healthy cent uninfected epidermal cells in the SCIDhu model subjects, but other viral proteins are also likely to be of VZV pathogenesis; blocking this IFN-a response recognized by VZV-specific T cells during acute vari- caused a dramatic increase in VZV spread in skin [4]. cella [10]. The adaptive immune response to primary Innate mechanisms of immune control have the ca- VZV infection also includes the induction of B cells pacity to maintain the host-virus equilibrium, despite that make VZV IgG and IgM antibodies, although the the VZV immune evasion strategies that inhibit both magnitude of this response does not correlate with the class I and class II major histocompatibility complex extent of varicella in healthy or immunodeficient chil- (MHC) mechanisms for antigen presentation to T cells dren, and B cell immunodeficiencies do not appear to while the virus is being transferred to skin and in early predispose to severe varicella [11, 12]. stages of cutaneous infection [4–6]. These strategies MEMORY IMMUNITY
The memory immune response that follows the reso-
Potential conflicts of interest: A.M.A. has received honoraria from Merck, the manufacturer of the varicella vaccine. lution of naturally acquired primary VZV infection is Financial support: supplement sponsorship is detailed in the Acknowledgments. characterized by the persistence of VZV IgG antibodies Reprints or correspondence: Dr. Ann M. Arvin, G312, Dept. of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305 and, in most cases, VZV IgA antibodies, as well as VZV- (aarvin@stanford.edu). specific CD4 and CD8 T cells [1]. VZV-specific IgG The Journal of Infectious Diseases 2008; 197:S58–60 antibodies have been shown to bind many VZV pro- 2008 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2008/19705S2-0006$15.00 teins and function to mediate neutralization and an- DOI: 10.1086/522123 tibody-dependent cytotoxicity. The overall frequency of
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VZV-specific memory T cells with proliferative capacity has been estimated to be ∼1:40,000 peripheral blood mononuclear cells [13]. These cells recognize VZV glycoproteins gE, gB, gC, and gH and the IE62 protein [7, 14, 15], and most produce IFN-g and tumor necrosis factor–a [16]. Among these pop- ulations are MHC class I– or class II–restricted cytotoxic T cells that recognize VZV proteins, including include gC, gE, gI, and IE62 and IE63 proteins [10, 13, 17, 18]. In VZV-immune subjects tested 120 years after varicella, the mean SD fre- quency of memory cytotoxic T cells specific for IE62 was 1: 105,000 85,000, and that for gE was 1: 121,000 86,000. The function of VZV IgG antibodies in protecting the host Figure 1. Importance of the initial “burst” of the adaptive host re- is presumed to be primarily the neutralization of infectious sponse for establishing long-term antiviral immunity. VZV, varicella-zoster VZV at sites of inoculation on reexposure to the virus by con- virus. tact with individuals who have varicella or herpes zoster (HZ). Should the virus evade this first line of defense as well as the in the naive healthy host was established in the prelicensure local innate responses, it is likely that VZV-specific T cells are
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clinical evaluations of the vaccine [23]. As expected, the mag- important for preventing symptomatic disease after exogenous nitude of these VZV-specific immune responses was related to reexposure. In addition, because VZV establishes latency in the infectious virus content and to the antigen content of the sensory ganglia, the adaptive T cell response is needed to pre- vaccine preparation [24, 25]. Host factors also play a role, in vent symptomatic reactivations of endogenous VZV. The com- that achieving responses in naive adolescents and adults that mon age-related decrease in VZV-specific T cells or a decrease were equivalent to those of younger children required the ad- resulting from immunosuppressive diseases or therapies is as- ministration of 2 doses of varicella vaccine. However, providing sociated with an increased risk of HZ [19]. One hypothesis is 2 doses to younger children resulted in higher VZV IgG an- that these exogenous and endogenous exposures to infectious tibody titers and T cell proliferation responses, and some evi- VZV may promote the maintenance of robust VZV memory dence, as reviewed by Watson [26] in this supplement, suggests immunity, because household exposure to varicella often results that memory responses were sustained more effectively. This in boosts in VZV humoral and cellular immune responses, and information has led to the recent recommendation to imple- HZ stimulates a dramatic increase in VZV IgG antibodies and ment a 2-dose regimen of varicella vaccine in all age groups VZV-specific T cell frequencies [20, 21]. Alternatively, the per- [27]. Because varicella epidemics have occurred annually in sistence of memory immunity may result from the initial clonal temperate climates and primary VZV infection appears to result expansion of VZV-specific T cells with helper and effector func- invariably in the establishment of latent infection, with the tions, without any requirement for subsequent restimulation potential for causing subclinical reactivation, it has not been in the immune host. possible to determine the relative importance of the primary VACCINE IMMUNITY host response and subsequent boosting for preserving protec- tive immunity against VZV. By comparison with other live According to current models, memory antiviral immunity is attenuated vaccines, such as measles vaccine, repeated exoge- thought to be a consequence of the magnitude of the expansion nous or endogenous contact with wild-type VZV will probably of effector cell populations elicited by primary exposure to the not be required to maintain persistent immunity. However, the pathogen [22] (figure 1). Memory immune responses are lower continuation of active and passive surveillance programs to when the initial immunologic “burst” is limited, because virus- monitor VZV infections in all age groups, as described in this specific effector cell populations are normally regulated to de- supplement, will make it possible to determine whether ad- crease during the weeks to months after primary sensitization ditional booster doses of varicella vaccine should be given. and expansion. The antigenic signal appears to be the most important factor in driving the expansion and, therefore, is expected to have direct consequences for the immunologic “set Acknowledgments point” of the memory immune response. VZV immune re- Supplement sponsorship. This article was published as part of a sup- sponses peak within a few weeks after naturally acquired in- plement entitled “Varicella Vaccine in the United States: A Decade of Pre- fection and decline to a persistent memory response with the vention and the Way Forward,” sponsored by the Research Foundation for Microbial Diseases of Osaka University, GlaxoSmithKline Biologicals, the characteristics described earlier. The capacity of the live atten- Sabin Vaccine Institute, the Centers for Disease Control and Prevention, uated varicella vaccine to elicit VZV IgG and T cell immunity and the March of Dimes.
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