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Keywords:

  • Antiviral immunity;
  • cell-mediated immunity;
  • cellular immunity;
  • cellular immunology;
  • immunotherapy;
  • cytomegalovirus (CMV);
  • cytome-galovirus infection;
  • Epstein-Barr virus (EBV);
  • herpes simplex virus;
  • herpes zoster;
  • HHV-6;
  • HHV-8

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Human herpesviruses including cytomegalovirus, Epstein–Barr virus, HHV6, HHV7, HHV8, Herpes simplex virus (HSV)-1 and HSV-2 and varicella zoster virus (VZV) have developed an intricate relationship with the human immune system. This is characterized by the interplay between viral immune evasion mechanisms that promote the establishment of a lifelong persistent infection and the induction of a broad humoral and cellular immune response, which prevents the establishment of viral disease. Understanding the immune parameters that control herpesvirus infection, and the strategies the viruses use to evade immune recognition, has been critical in understanding why immunological dysfunction in transplant patients can lead to disease, and in the development of immunological strategies to prevent and control herpesvirus associated diseases.


Abbreviations
CMV

cytomegalovirus

EBV

Epstein-Barr virus

HHV

human herpesvirus

HSV

herpes simplex virus

NK cell

Natural Killer cell

TLR

Toll-like receptor

VZV

varicella zoster virus

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Human herpesviruses have a unique capacity to establish a lifelong latent infection in the host, whereby the virus can persist within specific host cells, and protects itself from immune recognition by limiting viral gene expression [1]. Under certain clinical settings, the productive phase of infection is activated, resulting in lysis of the infected cell and release of viral progeny. These viruses have coevolved with the human host which has led to the development of a multifaceted antiviral immune response, driven by the complex array of strategies employed by these viruses to persist in the face of these challenges [2]. Evidence generated from human studies and murine models of herpesvirus infection have established a critical role for both innate and adaptive immunity, including both humoral and cell-mediated immune responses in controlling both primary and latent infection [3]. Natural killer (NK) cells and other innate mediators play a critical role in controlling infection before the establishment of an adaptive response, whereby neutralizing antibodies, typically targeting surface glycoproteins limit viral spread and CD4+ and CD8+ T cells control and destroy virally infected cells. Despite this, immune control is not sufficient to prevent the establishment of latency.

The human immune response is generally very successful at controlling infection and minimizing symptoms during primary and persistent infection; however, herpesviruses are responsible for several diseases including conditions associated with primary infection and malignancies triggered by the oncogenic properties of some herpesviruses [4, 5]. These clinical problems are more common and severe in immunocompromised individuals such as transplant patients on immunosuppressive medication and human immunodeficiency virus (HIV)-infected individuals, because of an impaired adaptive immune system (Table 1). Of particular importance is the potential role of herpesviruses in organ transplant rejection. Indeed, in the renal transplant setting, cytomegalovirus (CMV) can initiate cytopathic effect in glomerular and tubular epithelial cells and in capillary endothelial cells. Furthermore, increase in the expression of MHC class I on the engrafted tissue because of CMV infection can initiate acute rejection through the activation of cytotoxic T cells with concomitant alloantigen stimulation [6]. It is now firmly established that the development of severe herpesvirus-associated clinical complications in immunosuppressed individuals is often seen in individuals in whom T cell immunity is compromised emphasizing the importance of cell-mediated immunity in controlling herpes infections following the establishment of latency.

Table 1. Human herpesviruses infections and immune dysfunction in clinical disease
HerpesvirusClinical manifestation in immunocompetent hostClinical manifestation in transplant recipientsImmune dysfunction in clinical disease in transplant
Alphaherepesvirinae SimplexvirusRecurrent oral and genital ulcersHSV—Mucocutaneous diseases, systemic disease or encephalitis (rare) 
 HSV-1   
 HSV-2   
VaricellovirusChicken pox, zoster (shingles)VZV—Disseminated visceral disease,Loss of VZV-specific T cell
 VZV  meningoencephalitis, pain, scarring, postherpetic neuralgia, chicken pox, zoster (shingles) immunity
Betaherpesvirinae CytomegalovirusMononuelosis, congenital defects in unborn babiesCMV—Fever and neutropenia; lymphadenopathy, hepatitis,T function impairment and acquisition of markers of T cell
 CMV  thrombocytopenia, pneumonitis, gastrointestinal invasion (with diffuse colitis, gastritis, ulcers, and bleeding), pancreatitis, chorioretinitis meningoencephalitis exhaustion (e.g. PD-1)
RoseolovirusInfantile roseolaHHV6—Chronic allograft nephropathy,Lack of antigen-specific T cells in
 HHV6  bone marrow suppression, central both HHV6 and HHV7.
 HHV7  nervous system dysfunction, pneumonitis, hepatitis, increased severity of graft host disease Suppression of helper T cell response
  HHV7—Acute febrile respiratory disease, fever, rash, vomiting, diarrhea, low lymphocyte counts and febrile seizures 
Gammaherpesvirinae LymhocryptovirusMononucleosis, Burkitt's and other lymphomas,EBV—Posttransplantation lymphoproliferative disorder (PTLD)Impairment of latent antigen-specific T cell function
 EBV nasopharyngeal carcinoma  
RhadinovirusKaposi sarcoma, Castleman'sHHV8—Kaposi sarcoma, primary effusionTerminal differentiation of
 HHV8 disease, peripheral effusion lymphoma lymphoma, Castleman disease and plasmacytic proliferation virus-specific T cells (referred to as late phenotype)

In this review, we summarize our understanding of immune regulation of human herpesviruses and its potential implications in human transplantation and how this knowledge can be exploited to develop novel immunotherapeutic tools for the treatment of herpesvirus-associated diseases in transplant patients.

Innate Immunity to Human Herpesviruses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Innate immunity plays a critical role in the early control of herpesvirus infection [7]. Innate inflammation is classically characterized by the early production of inflammatory cytokines and chemokines that provide both antiviral effects and promote the induction of an adaptive immune response (see box 1 for mediators of innate immunity). Of critical importance for the induction of innate inflammation is signaling via pattern recognition receptors, that includes the family of Toll-like receptors (TLRs). Extracellular and intracellular pathogens are initially sensed as dangerous through the recognition of viral or bacterial determinants by these receptors, leading to a cascade that signals the induction of an inflammatory response. These signals are coordinated by the release of inflammatory cytokines and chemokines, including the type 1 interferons (IFN-α/β), interleukin 12 (IL-12) and tumor necrosis factor (TNF) [8]. These proinflammatory molecules function directly to delete virus or virally infected cells, recruit other inflammatory cells into the environment and activate antigen presenting cells to induce adaptive immunity. Studies in both animal and human herpesvirus models have shown that signaling can occur via a number of TLRs including TLR2, which recognizes virion components including surface glycoproteins [9, 10], TLR3, which recognizes dsRNA [11] and TLR9 which recognizes genomic DNA [12].

Box 1. Effector mediators of herpesvirus immunity

image

A role for “memory” NK cells and gamma-delta (γδ) T cells

The classical paradigm of immunological memory is that following primary infection, the memory compartment is comprised of antigen-specific CD4+ and CD8+ αβ T cells and antigen-specific memory B cells and plasma cells, and that these populations are maintained at a higher frequency with increased functionality or antigenic specificity to control repeated exposure to the same antigenic stimuli (Figure 2). Although this paradigm remains true, little attention has traditionally been paid to the impact viral infection has upon cellular mediators of innate immunity, and the consequences infection has for these innate mediators that includes NK cells, γδ T cells and other populations of invariant T cells, such as the NKT cells. A number of studies have shown that innate immune cells (e.g. NK cells) are highly resistant to posttransplant immunosuppression and may play an important role in controlling viral replication. Furthermore, recent observations have demonstrated a role for viral infection, and more specifically CMV, in imprinting a “memory signature” upon both NK cells and γδ T cells.

image

Figure 2. Immune control of herpesvirus infection. Primary infection with members of the herpesvirus family typically occurs via the mucosal epithelium. Primary infection is characterized by the production of virus particles which disseminate to the sites of latent infection, which are either of hematopoietic (monocytes, B cells and T cells) or neuronal origin. Primary infection is also characterized by the induction of a robust humoral and cellular immune response. During primary infection glycoprotein-specific B cells undergo somatic hypermutation and transition into long-lived plasma cells that secrete high affinity neutralization antibodies. Memory B cell populations are also generated that encode high affinity B cell receptors. Cellular immunity during primary infection is characterized by the activation of innate immune mediators including NK cells and invariant T cell populations, and the induction of adaptive antigen-specific αβ T cells following activation by professional antigen presenting cells (dendritic cells). These innate and adaptive cells transition into effector populations that induce lysis of virally infected cells; and memory populations that survey latently infected niches for infected cells. Following viral reactivation in these latent niches, both humoral (memory B cells, plasma cells and plasmablasts) and cellular mediators (innate and adaptive) reduce the viral burden via the neutralization of virus particles or the lysis of infected cells.

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NK cells express a complex array of stimulatory and inhibitory receptors that function to promote or suppress activation of the NK cell in response to ligands expressed on the surface of target cells [13]. Initial observations from a mouse model of murine CMV (MCMV) demonstrating that MCMV promoted the expansion of NK cells expressing the Ly49H receptor, which can recognize the MCMV m157 protein [14], were followed by studies in humans showing that CMV infection promoted the expansion of NKG2C+ NK cells [15]. NKG2C acts as an activating NK receptor that functions through recognition of HLA E molecules [15]. These observations were not evident in individuals only seropositive for Epstein–Barr virus (EBV) or HSV. Interestingly, these NK cells have recently been shown to share some phenotypic similarities with CMV-specific effector memory CD8+ T cells, characterized by the expression of CD57 [16, 17]. The NKG2C+ NK cells have the capacity to degranulate in response to stimulation via NKG2C and display a reduction in the expression of the inhibitory receptors, NKG2A and KIR3DL1. These observations demonstrate how CMV infection leaves a permanent imprint upon the NK cell population, potentially enhancing its capacity to control infection and viral reactivation. This improved capacity to control infection is supported by observations made using the MCMV model that have shown increased protection against MCMV challenge by memory phenotype NK cells [18].

γδ T cells are a distinct subset of T cells characterized by the expression of a restricted set of T cell receptors (TCR) composed of a γ-chain and a δ-chain, as opposed to the diverse array of α-chain and β-chain TCR associated with adaptive CD4+ and CD8+ T cell responses. Although the antigenic determinants that stimulate γδ T cells remain largely elusive, a number of studies have now demonstrated that infection with CMV can drive the long-term expansion of γδ T cells [19]. Subsequent studies demonstrated the preferential expansion of a restricted Vδ1 repertoire in γδ T cells by CMV [20], and an effector memory phenotype that is similar to that seen in CMV-specific αβ T cell populations [20, 21]. Furthermore, γδ T cell populations following CMV infection have been shown to display enhanced effector function, characterized by increased IFN-γ, granzyme and perforin expression and can degranulate following exposure to CMV-infected fibroblast cell lines [20, 22].

Adaptive Immunity to Human Herpesviruses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

The association between the immunosuppressed state required to maintain graft tolerance and the emergence of herpesvirus associated diseases in transplant patients played a pivotal role in defining the requirement for the establishment of an adaptive immune response to control the spread of latent reactivating virus. Research over the past two decades has subsequently provided significant insight into the nature of adaptive cellular immunity generated in response to herpesvirus infection.

As is the case with most viral infections, adaptive immunity to herpesviruses is characterized by the induction of a strong antibody, and effector CD4+ and CD8+ T cell response (Figure 2; and see box 1 for a summary of the cellular mediators of adaptive immunity to herpesviruses). Following resolution of acute infection, contraction of the effector response ensues, resulting in the establishment of immunological memory. However, unlike other viral infections, whereby the establishment of sterility leads to a dramatic contraction in the memory response, reactivation during herpesvirus latency drives the maintaining of a high frequency of circulating lymphocytes. It has also become evident that the nature of the latent lifecycle of the herpesvirus dictates the frequency and functional properties of these memory populations (Figure 3).

image

Figure 3. Frequency and phenotypic properties of herpesvirus-specific T cells. (A) Diagrammatic representation of the relative frequency of herpesvirus-specific CD8+ and CD4+ T cell populations in the peripheral blood of healthy virus carriers. (B) Phenotypic properties of herpesvirus-specific T cells in blood and in peripheral tissues.

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T cell immunity to CMV

The T cell memory compartment in the peripheral blood of CMV-seropositive healthy donors is dominated by T cells specific for CMV-encoded lytic cycle antigens, with greater than 40% of the peripheral blood T cell repertoire in some elderly individuals specific for CMV-encoded antigens [23, 24]. Characterization of the T cell responses in both healthy human donors and MCMV models has shown that CMV-specific T cell immunity inflates over time [24-27]. Although memory inflation of T cells specific for other herpesviruses may occur, the high frequency of CMV-specific CD8+ T cells and to a lesser extent CMV-specific CD4+ T cells is unique and is not evident in donors asymptomatically infected with other herpesviruses [23, 28]. It is thought that constant viral reactivation from latently infected monocytes and other nonhematopoietic viral reservoirs drive this dramatic CMV-associated memory inflation [29-32]. In concordance with the high frequency of CMV-specific T cells in the peripheral blood of CMV-seropositive individuals, CMV-specific T cells also display a highly differentiated phenotype. Cells displaying the classical phenotypic and functional hallmarks of effector memory cells predominate within the CMV-specific T cell population. These cells are characterized by a loss in expression of the costimulatory molecules, CD27 and CD28, and a loss of expression of the IL-7 receptor, CD127, resulting in a reduced capacity to respond to IL-7 driven homeostatic proliferation [33-35]. CMV-specific T cell populations also display high levels of the senescence associated marker CD57 [35-37], and while they retain the capacity to proliferate in response to antigen they require the addition of either CD4+ T cell help or cytokine for optimal expansion [38]. However, despite phenotypic similarities with effector T cells detected in other chronic viral infections, CMV-specific T cells in healthy individuals do not show other hallmarks of chronically activated T cells, such as the high levels of expression of inhibitory markers, such as the programmed death (PD)-1 receptor [39, 40]. CMV-specific T cells are also functionally competent, demonstrated by the capacity to express a full array of effector cytokines, including TNF, IFN-γ, MIP1-β and IL-2 and display immediate cytolytic effector function in response to antigenic stimulation [41-43]. This immediate cytolytic effector function is driven by the presence of preformed cytolytic granules containing Perforin and granzyme B [44, 45]. Despite this bias toward effector memory populations in the peripheral blood, recent observations in lymph nodes have suggested that CMV-specific T cell populations in secondary lymphoid organs display a central memory phenotype [46]. A proportion of CMV-specific T cells in the peripheral blood of most donors can also display a similar central memory phenotype. Therefore although the functional differentiation of effector CMV-specific T cell populations in the peripheral blood is likely required to maintain a high degree of immunosurveillance to control constant viral reactivation, the maintenance of central memory populations in secondary lymphoid tissue provides a source of cells for self-renewal.

The complexity of CMV has led to a significant amount of work investigating the source of antigenic peptides recognized by CMV-specific T cells during the lytic cycle of infection. Early studies indicated that immunodominant T cells responses are predominantly directed against phosphoprotein (pp) 65 and the immediate early (IE)-1 protein [47-49]. These two proteins remain the immunodominant antigens recognized by CMV-specific T cells, however, more thorough analysis of the CMV-specific T cell repertoire has revealed that immunodominant T cell responses are also directed against an array of other antigens, including pp28, pp50, pp150 and the surface glycoproteins, gH and gB [50]. In addition, recent studies have demonstrated that CMV-specific T cell immunity is generated against latent lifecycle antigens, including UL138 [51]. These observations, and studies demonstrating that up to 70% of the open reading frames of CMV may be targeted by the T cell immune response [52], further emphasize the complexity of CMV-specific T cell immunity.

T cell immunity to EBV and other human herpesviruses

Although EBV infection does not induce the level of T cell memory inflation that is associated with CMV infection, its unique life cycle and capacity to latently transform B cells has provided significant insight into the role T cell immunity plays in controlling EBV infection [53]. Recent observations have also provided insight into the unique phenotypic properties of EBV-specific T cells that specifically promote immunosurveillance of infected B cells and is dependent upon the expression of the SLAM-associated protein [54-56]. EBV-specific T cells are typically not as functionally differentiated as CMV-specific populations, retaining the expression of the costimulatory molecules CD27 and CD28 and displaying a reduced capacity for immediate cytolytic function [33, 44, 57]. Unlike CMV-infection in which a breakdown in immunosurveillance by T cells specific for lytic cycle antigens likely leads to disease in immunocompromised individuals, the association of immune compromise with uncontrollable proliferation of EBV-transformed B cells suggests that T cells recognizing latently infected cells are the critical mediators in controlling EBV-associated disease. EBV latency is associated with the expression of the EBV nuclear antigens (EBNA) 1–6, and the latent membrane proteins (LMP) 1 and 2 [58]. Extensive analysis has provided a thorough characterization of the immunodominance hierarchy of the EBV latent associated antigens [53, 59]. Immunodominant T cells responses in most healthy individuals are directly toward EBNA3–6. These antigens are highly immunogenic and can be efficiently recognized in EBV-transformed lymphoblastoid cells lines by specific T cells. Conversely, subdominant T cell responses are generated against EBNA1, LMP1 and LMP2, which play critical roles in establishing and maintaining latency, and are not as efficiently recognized in EBV-transformed lymphoblastoid cells lines [60-63]. Although the role of T cells specific for lytic cycle antigens in controlling EBV-associated malignancies in immunocompromised settings is less clear, T cell immunity to lytic cycle antigens likely play an important role in controlling primary infection. Immunodominant T cell responses are generated in response to the IE lytic cycle proteins BZLF1 and BRLF1, and less dominant responses can also be detected against a diverse array of other antigens, including the early antigens BMLF1 and BMRF1, and to the surface glycoproteins, including gp350 [53, 64]. Although less well defined, immunity to the other human gammaherpesvirus, HHV8, which is also associated with malignancies in immunocompromised individuals, appears to be dependent upon the induction of responses to both lytic and latent cycle antigens [65-67].

T cell immunity also plays a critical role in immunosurveillance of the members of the alphaherpesvirus family, which includes VZV, HSV-1 and HSV-2. Similar to CMV, analysis of the cellular responses to VZV and HSV has primarily focused upon lytic cycle antigens. These studies have also demonstrated diversity in the antigenic targets of HSV and VZV-specific T cells, with immunodominant responses generated in response to both structural antigens, including tegument proteins and surface glycoprotein and nonstructural antigens [68, 69]. Phenotypically, HSV and VZV-specific T cells in asymptomatically infected donors more closely resemble EBV-specific T cell populations, although their frequency is generally an order of magnitude lower [70-72]. Observations have also shown that HSV-specific T cells have the capacity to localize in latently infected human trigeminal ganglia [73, 74]. However, VZV-specific T cell could not detected, despite the presence of VZV latently infected neurons. The HSV-specific T cell populations in the ganglia display reduced expression of CD27 and CD28, which is indicative of an effector memory phenotype and also show signs of more recent activation via an increased expression of CD69 relative to HSV-specific T cells in the peripheral blood. EBV-specific T cells with a distinct effector function have also been shown to be enriched in tonsillar tissue, a site of EBV infection and reactivation [75]. In animal studies, HSV-specific T cells have been shown to have the capacity to inactivate HSV in infected neurons via a noncytolytic mechanism, that was dependent upon granzyme B mediated degradation of the HSV IE protein ICP4 [76]. Therefore, despite similarities between the antigenic targets of T cells induced in response to the different herpesvirus infection, the lifecycle of each virus has a distinct impact upon the location, frequency, phenotype and functional properties of the memory T cell populations that develop following infection.

Humoral immunity to human herpesviruses

The humoral immune response generated in response to herpesviruses is characterized by the generation of long-lived memory B cells and antibody secreting plasma cells. However, similar to observations made in T cells, the kinetics and frequency of humoral immunity differs with each herpesvirus. A recent comprehensive analysis of the antibody responses to VZV and EBV in infected individuals has provided significant insight into the kinetics of the humoral immune response to these viruses [77]. Interestingly, although EBV-specific antibody titers were shown to be stable over time, with a half-life that far exceeded human life expectancy and only rare episodes of antibody spikes, VZV antibody titers had a half-life of 50 years, despite evidence suggesting frequent viral reactivation. In the context of CMV infection, it was recently demonstrated that similar to memory inflation in the T cell compartment, antibody titers and memory B cells in humans increase over time [78, 79]. Recent analysis has also demonstrated the relatively high frequency of CMV-specific cells that can be detected in the memory B cell compartment of seropositive individuals [80]. These observations further support the notion that it is the nature and the frequency of the antigenic stimulus that dictates the size and function of the adaptive immune response generated in response to herpesvirus infection.

Analysis of the antigenic targets following herpesvirus infection has revealed that antibody responses are generated against a diverse array of antigens, including nonneutralizing antibody responses that target viral capsid antigens and nonstructural antigens from both the lytic and latent lifecycle of the virus. However, current research into the role of antibody in the control of infection has focused upon antigenic targets that induce virus neutralization. These neutralizing antibody targets are comprised of the surface glycoproteins that facilitate viral entry into the target cells. The predominant targets of CMV neutralization include glycoprotein (g) B, and the gH/gL complexes [81-83]. Although gB remains the predominant target for vaccine formulations [84], some controversy remains as to the most effective target for CMV neutralization. Despite this, emerging literature on the response to genotypic variants of glycoprotein B is providing insight into the complexity of infection, coinfection and reinfection with distinct strains of CMV [85-87]. These studies have shown that antibodies specific for distinct strains of CMV can be detected in infected individuals and that new non-crossreactive antibody can emerge in infected donors over time. However, in the context of VZV, genotypic diversity does not necessarily impact on cross-neutralization of different genotypes. Recent observations suggest that despite sequence differences in the glycoproteins of the vaccine Oka strain of VZV and strains present in European populations, antibodies generated following vaccination with Oka retain the capacity to neutralize virus from distinct genotypes [88]. These observations imply that although preexisting humoral and cellular immunity may not prevent reinfection with genotypically distinct variants of CMV, cross-neutralizing antibodies can be generated in response to other herpesviruses.

In the context of other herpesvirus infection, viral neutralization of EBV is thought to be generated via targeting gp350, which facilitates entry into B cells and research into neutralization targets of HSV has primarily focused upon gD. However, recent results from vaccine studies have provided conflicting evidence for the effectiveness of these molecules as neutralization targets in the prevention of infection [89, 90]. Vaccination with gp350 did not reduce the incidence of EBV infection, despite the generation of high titer neutralizing antibodies, but did reduce the incidence of EBV-associated infectious mononucleosis. Similarly, despite promising results from early clinical studies [91], vaccination with gD did not reduce the incidence of HSV-2 infection. Nevertheless, although gp350 and gD-specific antibodies may not be able to prevent infection, which may be facilitated via a number of surface receptors, they likely still play an important role in the control of disease caused by primary EBV and HSV infection, respectively.

The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Coevolution over millennia has lead to the establishment of an effective balance following herpesvirus infection between viral immune evasion mechanisms and host immune control mechanisms. It is this balance that allows the successful establishment of latency by herpesviruses and that prevents in most healthy individuals the uncontrolled viral spread and disease that is evident in immunocompromised patients.

Upon primary infection herpesviruses deploy an arsenal of immune evasion mechanisms to prevent their eradication before the successful establishment of latency [5]. These evasion strategies are focused on suppression of both innate activation and the induction of adaptive immunity. The suppression of innate activation following herpesvirus infection occurs via pathways dedicated to the recognition of foreign pathogens. CMV and the other herpesviruses are known to encode a number of genes that can function to subvert inflammation. These include viral homologues of the human immunosuppressive cytokine IL-10, encoded by both CMV and EBV [92, 93], and chemokine receptor homologues, such as CMV-encoded US28 [94]. Human CMV also encodes a number of other genes that prevent or restrict activation of other mediators of innate inflammation, including NK cells. A number of CMV-encoded proteins, including UL16, restrict cell surface expression of MICA, MICB and the ULBPs, which are upregulated upon infection and activate NK cells via the NKG2D pathway [95]. Conversely, the CMV-encoded UL40 protein promotes cell surface expression of HLA E, which functions as an inhibitory receptor for NK cells via NKG2A [96].

In addition to mechanisms to suppress innate activation, CMV and the other herpesviruses demonstrate a broad array of strategies to restrict recognition by the adaptive immune response. CMV encodes a number of genes that suppress the presentation of CMV-encoded proteins. These include viral IL-10, which downregulates MHC class I expression, US2 and US11 that target MHC class I molecules for degradation [97, 98], US6 and US3 which inhibit the function of the transporter associated with antigen processing (TAP) and its accessory molecule tapasin [99, 100], and US10, which delays transport of MHC molecules into the endoplasmic reticulum [101]. Recent studies have also begun to elucidate the role viral microRNAs play in CMV mediated immune evasion [102]. The other members of the herpesvirus family have also developed an array of similar strategies to limit antigen presentation (see box 2).

Box 2. Herpesvirus immune evasion strategies and counter evasion strategies of the host

image

The primary focus of the herpesvirus immune evasion strategies appear targeted at suppressing immune recognition during primary lytic infection and upon viral reactivation, thus promoting the successful establishment of latency upon primary infection or the survival of virus following reactivation for transmission and establishment of latency in a new cell or host. In contrast to the diverse array of immune evasion strategies evident during the lytic stages of infection, latent infection appears less reliant upon mechanism that directly suppress immune function. Although CMV viral IL-10 is expressed during latency, and may function to limited activation of latently infected monocytes [103], immune evasion during latency appears primarily reliant upon immune ignorance induced by minimal protein expression and the expression of poorly immunogenic antigens [61, 63, 104]. Despite the wide array of immune evasion strategies that are deployed following herpesvirus infection, an equilibrium is typically reached, whereby primary infection is eventually controlled through the deployment of multiple arms of the immune response, and reactivating virus, while still capable of evading immune control to promote transmission to another host, is kept in check by both adaptive and innate memory cell populations. However, disequilibrium can occur in settings of immune compromise, such as in transplant patients, whereby profound immunosuppression can prevent the induction of protective cellular responses during primary infection or lead to dysfunction in memory T cell populations during chronic antigen exposure following viral reactivation.

Herpesvirus Immunity and Transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

A direct role of virus-specific T cell responses in prevention of viral reactivation and/or proliferation of virus-infected cells (e.g. EBV), was first demonstrated in the transplant setting. Indeed, it is well established that solid organ transplant recipients who lack preexisting immunity are at the highest risk of developing herpesvirus-associated diseases when engrafted with an organ from a seropositive donor. Furthermore, pioneering studies by Riddell et al. showed that adoptive transfer of donor-derived virus-specific CD8+ T cells restricted through HLA class I alleles shared by the donor and the recipient successfully reconstituted CMV-specific T cell responses in transplant recipient and prevented viral reactivation and disease [105]. One of the interesting features of this study was that this immune reconstitution of CMV-specific CD8+ T cell immunity declined after a few weeks, suggesting that helper T cell function is required to maintain long-term virus-specific CD8+ T cell immunity. Indeed subsequent studies showed that adoptive transfer of virus-specific CD4+ and CD8+ T cells stimulated with autologous CMV antigen sensitized autologous antigen presenting cells readily reconstituted virus-specific immunity with massive expansion of CMV-specific T cells in vivo [106]. These T cell-based therapies have also been successfully used for other herpesviruses such as EBV-associated malignancies in transplant patients [107-109].

Taking a clue from these successful immunotherapy studies, a number of groups have conducted detailed analysis of herpesvirus-specific T cell immunity in transplant patients to precisely delineate the mechanisms of immune regulation and use this knowledge to develop better diagnostic tools and therapeutic strategies [110]. Over the last decade, a number of new technologies such as peptide-MHC multimers, intracellular cytokine assay and ELISPOT have dramatically revolutionized the ex vivo analysis of virus-specific T cell responses [111, 112]. Using these techniques a number of studies have demonstrated that the functional and phenotypic profile of virus-specific CD4+ and CD8+ T cells correlates with protection from herpesvirus-associated diseases in transplant patients [3, 113]. Indeed, longitudinal analysis of CMV-specific T cell responses in solid organ transplant patients revealed that protection from symptomatic viral reactivation was critically dependent on the stable maintenance of functional antigen-specific T cells [114-116]. In contrast, CMV-specific T cell responses in transplant patients with recurrent symptomatic CMV disease or reactivation showed significant fluctuations in the levels of IFN-γ expressing CD8+ T cells. More importantly, the reduction in IFN-γ expression by antigen-specific T cells preceded the clinical diagnosis of active disease [114]. Subsequent studies by Mattes et al. have also shown that loss of IFN-γ expression by virus-specific CD8+ T cells were predictive of high levels of CMV replication, and the functional impairment was evident before the detection of viral DNA [117]. In depth analysis of the precise antigen specificity of virus-specific T cells revealed that protection from viral reactivation correlates with high frequencies of IE-1 but not pp65-specific CD8+ T cells [118]. These conclusions have been disputed by other studies which indicate that pp65-specific T cells are also critical in preventing CMV reactivation [114]. Analyses of EBV-specific T cell responses in solid organ transplant patients have indicated that reconstitution of latent antigen-specific T cells are crucial for protection against posttransplant lymphoproliferative disease [119].

A combination of ex vivo functional analysis with cell surface expression of phenotypic markers and transcriptional regulators has allowed the identification of functionally distinct T cell populations, at both different stages of T cell differentiation and phases of disease. An increased expression of CD38 and loss of IFN-γ expression was observed in virus-specific T cells from solid organ transplant patients with active CMV disease [114]. These observations were consistent with earlier studies demonstrating that an increased expression of CD38 on CD8+ T cells was coincident with the progression of HIV-associated disease. More recent studies have shown that liver transplant patients who lacked immune control with relapsing viremia during early chronic infection showed poor induction of T-box transcription factor (T-bet) and lower frequencies of virus-specific effector T cells during primary infection. T-bet is a critical transcriptional regulation of T cell function and maturation [120]. Another potential marker, PD-1 has also been identified as a prognostic indicator of CMV disease in transplant patients. Increased expression of PD-1 on virus-specific CD8+ T cells correlates with high levels of viral reactivation [121]. Hertoghs et al. carried out gene expression analysis in virus-specific T cells at different stages of infection from a small cohort of CMV-seronegative renal transplant who received grafts from seropositive donors [122]. These studies showed that CMV infection induced dramatic changes in the transcriptomes of antigen-specific T cells which included enhanced cell cycle and metabolic activity during the acute phase of infection and up-regulation of the transcription factors T-bet and eomesodermin. In addition, strong expression of cytolytic proteins (granzyme B and perforin) and chemokine receptors (CX3CR1) were found during all stages of infection. These studies provide an important platform for further in-depth assessment of potential clinical and diagnostic relevance of functional and phenotypic profiling in transplant patients. Over the last few years, a number of novel diagnostic tools have been developed which allow ex vivo analysis of herpesvirus-specific T cells and some of these techniques have shown predictive potentiality to identify transplant patients who are at higher risk of developing infectious complications [3, 110]. Of particular interest is the QuantiFERON®-CMV assay (Cellestis Ltd., Melbourne, Australia) which allows ex vivo assessment of CMV-specific T cell immunity in the whole blood [123]. These studies have shown that QuantiFERON®-CMV is a highly specific and sensitive assay. A number of clinical studies have assessed the potential application of this assay in identifying transplant patients who are at increased risk of developing CMV-associated complications. Indeed, lung transplant patients who showed poor CMV-specific immune responses based on the QuantiFERON®-CMV assay developed significant viral reactivation in the lung allograft [124]. Similarly, Kumar et al. have shown that a positive QuantiFERON®-CMV assay at the end of prophylaxis correlated with protection from subsequent symptomatic CMV disease in solid organ transplant disease [115]. Based on these studies, it has been proposed that the QuantiFERON®-CMV assay can be used to predict progression versus spontaneous clearance of CMV reactivation in transplant patients and may assist in clinical decisions related to anti-HCMV prophylaxis or therapy.

Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Adoptive immunotherapy based on both humoral and cellular immune responses have been used as therapeutic/prophylactic tools for the prevention/treatment of herpesvirus-associated complications in transplant patients. Adoptive transfer of CMV-specific hyperimmune globulin (CMVIG) has been shown to reduce the incidence of virus-associated syndromes in renal transplant patients and also increase the survival of liver transplant recipients [125, 126]. Comprehensive analysis of multiple randomized trials demonstrated a beneficial effect of the prophylactic use of CMVIG on total survival and prevention of CMV-associated death in solid organ transplant recipients. CMV disease was significantly reduced in all recipients receiving prophylactic CMVIG, although no impact on CMV infections and clinically relevant rejections was observed [127].

Reconstitution of cellular immunity in transplant patients using adoptive T cell therapy was instigated following studies in murine models of MCMV and EBV in which adoptive transfer of CD8+ T cells protected against virus-associated diseases [128]. Over the last two decades, T cell-based therapies have also been successfully used for herpesviruses-associated diseases in transplant patients [129-132]. There is an increasing argument that T cell-based immunotherapy should be considered as a combination therapy with chemo/radiotherapy particularly in advanced disease to improve survival [133]. It is important to mention here that long-term implementation of adoptive immunotherapy based on autologous T cells has remained significantly constrained by the delay between the diagnosis and delivery of T cell therapy. This process requires rigorous in vitro manipulation and often the quality of T cell therapy prepared from transplant recipients fails to meet the therapeutic criteria because of low lymphocyte counts or poor expansion of antigen-specific T cells. More recently, a number of groups have proposed alternative strategies which may dramatically improve the potential use of T cell-based therapies for infectious complications in transplant patients. One such strategy proposed by Paul Moss et al. involves ex vivo enrichment of virus-specific T cells using peptide-MHC multimer technology [134]. This strategy was successfully used by this group to treat eight/nine stem cell transplant patients. Extension of this technology to solid organ transplant patients may be difficult because of various technical roadblocks including the availability of clinical grade peptide-MHC multimers and low lymphocyte counts in transplant recipients. To overcome the limitation of clinical grade peptide-MHC multimers, ex vivo capture of antigen-specific T cells using IFN-γ secretion technology developed by Miltenyi Biotech GmBh (Gladback, Germany) has also been tested in the clinical setting, with highly encouraging outcomes especially in the prophylactic setting. Another alternative strategy, originally developed by Dorothy Crawford et al., involves the adoptive transfer of HLA-matched allogeneic virus-specific T cells. This strategy has been successfully used for the treatment of EBV-associated lymphomas, and this therapeutic effect was observed over many years after adoptive immunotherapy [135]. These observations have been reproduced and extended by Helen Heslop et al. This group have successfully used allogeneic multivirus-specific allogeneic T cells which included both EBV- and CMV-specific T cells for the treatment of transplant patients [136]. There are a number of groups around the world who are now further refining the technology of in vitro expansion of virus-specific T cells and expand the therapeutic potential of these T cells to target other herpesviruses including HSV, HHV6 and HHV8. It is anticipated that within next decade, adoptive immunotherapy will be available as an “off-the-shelf” therapy for the majority of transplant patients both as a prophylactic and/or therapeutic tool.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions

Rajiv Khanna is supported by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. This work is supported by The Roche Organ Transplantation Research Foundation (ROTRF) and the National Health and Medical Research Council (Australia).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions
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Questions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Innate Immunity to Human Herpesviruses
  5. Adaptive Immunity to Human Herpesviruses
  6. The Interplay Between Immune Evasion and Immune Control in Herpesvirus Infection
  7. Herpesvirus Immunity and Transplantation
  8. Exploiting Immune-Based Therapeutic Strategies for Prevention and Treatment of Herpesvirus-Associated Diseases in Transplant Patients
  9. Acknowledgments
  10. Disclosure
  11. References
  12. Questions
  1. What types of immune cells are crucial during early stages of herpesvirus infection before the adaptive immunity is established?
    1. NK, NKT and γδ T cells
    2. NK, CD4 T cells and B cells
    3. CD8, NK and NKT cells
    4. CD8, CD4 and B cells
  2. What type of receptor does the innate immune system use to sense herpesvirus infections?
    1. Immunoglobulin
    2. B cell receptor
    3. Toll-like receptor
    4. Type 1 interferons
  3. What molecules do effector T cells secrete to kill virus-infected cells?
    1. T cell receptor
    2. Immunoglobulin
    3. Perforin and Granzyme
    4. CD27 and CD28
  4. How can you recognize T cell dysfunction in transplant patients following active herpesvirus infection?
    1. Increased interferon γ production and up-regulation of PD-1
    2. Lack of interferon γ production and up-regulation of PD-1
    3. Lack of interferon γ production and down-regulation of PD-1
    4. Increased interferon γ production and down-regulation of PD-1