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Keywords:

  • Epidemiology;
  • herpesvirus;
  • immunosuppression;
  • latency;
  • opportunistic infection;
  • trans-plantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed.


Abbreviations
CMV

cytomegalovirus

EBV

EpsteinBarr virus

EBERs

EBV encoded small nuclear RNAs

HSV-1 and -2

herpes simplex virus-1 and -2

HHV

human herpesviruses

HHV6A and HHV6B

human herpesvirus variant 6A and human herpesvirus variant 6B

HHV-7 and -8

human herpesvirus-7 and -8

KSHV

Kaposi's sarcoma

LAT

latency associated transcripts

MHC

major histocompatibility complex

miRNA

microRNA

NAT

nucleic acid testing

PTLD

posttransplant lymphoproliferative disorders

VZV

varicella zoster virus

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The clearest demonstration of the dynamic interaction between infectious pathogens and the human immune system is seen in the manifestations of herpesvirus infections in organ transplantation [1, 2]. Most of the current knowledge of cytomegalovirus (CMV) and other herpesviruses in transplantation is recent—this includes the original descriptions of the manifestations of CMV in transplantation. The virologic basis of Kaposi's sarcoma was proposed based on epidemiologic studies in AIDS patients with the first description of human herpesvirus 8 (HHV8) as the causative agent of Kaposi's sarcoma (KSHV) in 1994 by Moore and Chang [3-5]. The rapidity of advances in the diagnosis, treatment and understanding of the biology of the herpesviruses necessitate periodic reviews of this topic by even expert clinicians.

The family Herpesviridae was created to include three main subfamilies (Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae); this was subsequently elevated to the order Herpesvirales. Herpesviruses are present in most animal species [6]. Those identified in humans include herpes simplex virus-1 and herpes simplex virus-2 (HSV-1 and -2), varicella zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus variant 6A and human herpesvirus variant 6B (HHV6A, HHV6B), human herpesvirus-7 (HHV-7) and human herpesvirus-8 (KSHV or HHV-8). These are summarized in Table 1. While human viruses are the focus of this discussion, it is worth noting in that some of the nonhuman species of this order also cause significant infection in humans, including the monkey herpes B virus (Cercopithecine herpesvirus-1 or CeHV-1 from macaques), and the Murine gammaherpesvirus-68 or MHV-68. CeHV-1 may cause fatal encephalitis while MHV-68 may cause false-positive serologic assay reactions with the human herpesviruses.

Table 1. The human herpesviruses (HHV)
TypeCommon nameMajor syndromesSite of latencyMeans of spread
α (Alpha) herpesviruses: rapid reproduction and cell lysis in vitro, rapid cell lysis and spread in vivo, primary target mucoepithelial cells, latency in sensory ganglia
HHV-1Herpes simplex virus-1 (HSV-1)Oral herpes, genital herpes (predominantly orofacial), as well as other herpes simplex infectionsSensory and cranial nerve gangliaClose contact (sexually transmitted disease)
HHV-2Herpes simplex virus-2 (HSV-2)Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infectionsSensory and cranial nerve gangliaClose contact (sexually transmitted disease)
HHV-3Varicella zoster virus (VZV)Chickenpox and shinglesSensory and cranial nerve gangliaRespiratory and close contact (including sexually transmitted disease)
γ (Gamma): replication in lymphoblastoid cells, lytic cycle in some fibroblasts and epithelial cells
HHV-4Epstein–Barr virus (EBV), lymphocryptovirus (gamma-1-herpesvirus)Infectious mononucleosis, Burkitt's lymphoma, CNS lymphoma, posttransplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy leukoplakiaMemory B cellsClose contact, transfusions, tissue transplant and congenital
HHV-8Kaposi's sarcoma-associated herpesvirus (KSHV), human rhadinovirus (gamma-2-herpesvirus)Kaposi's sarcoma, primary effusion lymphoma, some types of multicentric Castleman's diseaseB cellsClose contact (sexual), saliva?
β (Beta): long replication cycle in vivo and in vitro, limited host range, large infected cells, latency in mononuclear cells, secretory cells, some epithelial cells, others
HHV-5Cytomegalovirus (CMV) Monocyte, lymphocyte and epithelial cellsInfectious mononucleosis-like syndrome,[10] retinitis, etc.Monocytes, macrophages, lymphocytes, othersSaliva
HHV-6A and HHV-6BRoseolovirus, Herpes lymphotropic virus T cells, other cellsSixth disease (roseola infantum or exanthem subitum)T, B, NK cells, monocytes, macrophages, liver, salivary endothelial, neuronal cellsRespiratory and close contact?
HHV-7Roseolovirus T cells, other cellsSixth disease (roseola infantum or exanthem subitum)CD4+ T cells, salivary epithelial, lung, skin cells?

Viral Structure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

In the herpesviruses the icosahedral viral capsid is surrounded by a layer of protein called the tegument and an outer lipid bilayer envelope studded with glycoproteins [7]. These proteins include the main targets of the immune response and for vaccine development. Herpes virions contain large double-stranded, linear DNA genomes of 125 to 229 kb and encoding up to 200 genes [8]. These genes include a “core” of approximately 40 proteins that are conserved among all of the herpesviruses, including proteins involved in nucleic acid synthesis (e.g. viral DNA polymerase) and virion structure (major capsid proteins, glycoproteins B, H and L). Each of the subfamilies share a physical order of the genes within the genome and an additional set of conserved genes encoding proteins associated with the unique properties of the subfamily: latency transcripts (alpha- and gammaherpesviruses), early gene expression (HSV) or viral entry. Herpesvirus genomes include both long unique regions and repeated shorter regions. Restriction digests of the repeated elements coupled with sequence polymorphisms may be used in molecular epidemiologic studies to determine (e.g.) whether a virus is donor or host derived [9]. The large size of the genome allows inclusion of a variety of additional gene products that impact the virus–host interaction and contribute to successful parasitism in the human host [10, 11].

General Properties and Patterns of Replication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The human herpesviruses share a number of important general properties;

  1. Viral nucleic acid replication and capsid assembly occurs in the host cell nucleus. The virion is further processed in the cytoplasm.
  2. Productive infection of virus results in lysis of the host cell (“lytic infection”). Lytic replication of herpesviruses generally inhibits RNA and protein synthesis of the host cell.
  3. The herpesviruses have the capacity to establish latent infection (‘latency’) in their hosts. This is a critical concept in immunocompromised hosts. Latent virus exists as closed circular DNA, expressing a minor subset of viral genes often referred to as a “latency program”. Within a single host, virus may cause productive infection in one subset of cells and establish latency in others. The corollary to this observation is that herpesviruses may be activated from latency, but the essential stimuli for this event are not clear. Active, lytic viral replication may be asymptomatic (e.g. shedding of virus from mucosal sites) or symptomatic. The marker for lifelong, latent infection is the presence of antibody to the virus, a positive serologic assay.
  4. Herpesviruses encode a large number of gene products that support viral replication including those for DNA synthesis (e.g. DNA polymerase), regulatory genes and nucleic acid metabolism (e.g. thymidine kinase) and structural proteins (e.g. capsid and virion proteins). Other gene products serve to subvert the host's immune responses [10, 11]. Great variability exists in the array of gene products produced by each subtype of herpesvirus. Many genes appear to have been acquired as the result of coevolution with their hosts (e.g. the interleukin-10 homolog of CMV) [12-14]. The functional properties of multiple genes are conserved between the human herpesviruses (e.g. regulatory genes, DNA polymerase), although the specific genomic sequences vary.

Despite these shared properties, the herpesviruses vary in the specific cell types in which lytic and latent infection are established (Table 1) and in the clinical syndromes they produce. Different subsets of viral genes are transcribed based on whether or not infection is lytic or latency is established. Lytic infection usually leads to production of viral genomes, new viral particles and cell death. Latency is associated with the production of a limited array of “latency associated transcripts” (LAT) and persistence of the viral genome within the cell with the potential for reactivation at a later time. The clinical manifestations of primary infection or reactivation infection depend on the cells infected and the adequacy of the host's immune response to the virus.

Infection, Host Range and Viral Latency

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The overall scheme for viral infection and reactivation is conserved between herpesviruses. Infection is initiated when a viral particle contacts a cell with the appropriate surface receptor molecules for the surface glycoproteins of the virion. The virion is then internalized, dissociates and the viral DNA migrates to the cell nucleus. Virus may also enter cells by endocytosis; subsequently, fusion of the virion envelope to the endocytic membrane allows discharge of the nucleocapsid into the cell cytoplasm. In the nucleus, the linear viral DNA circularizes and replication begins.

Each of the herpesviruses has a well-specified host range for lytic and latent infections. Beyond the natural targets of infection, some studies have demonstrated the ability to “force” some viruses into new cell types or even between species in vitro. Host range is determined both by the distribution of cell surface receptors as well as supportive intracellular conditions that remain to be defined.

The mechanisms used by the herpesviruses to establish and maintain latency are incompletely understood. The herpesvirus genomes exist as circular, episomal elements in latency. Latency transcripts protect the virus from endogenous cellular protective mechanisms including cellular apoptosis (programmed cell death) and antiviral alpha-interferon production [15]. It appears that expression of viral microRNAs (miRNAs) may also control aspects of the host cellular gene expression (e.g. LMP1 from EBV appears to control the production of a series of novel miRNAs); alterations in the methylation of viral histone proteins may downregulate lytic gene expression to preserve latency [16-19]. As an alternative, some viral pro-lytic regulatory proteins are expressed but sequestered outside the nucleus to prevent their activation of expression of host and viral lytic genes. Special latency transcripts have unique functions. In EBV, latency transcripts are required for the transformation and immortalization of B-lymphocytes. The EBV nuclear antigen 1 protein allows latent viral episomes to partition to dividing infected B cells. HSV expresses latency-associated noncoding transcripts that interfere with cellular apoptosis. VZV latency proteins inhibit antiviral interferon-α. EBV and KSHV encode unique latency proteins in malignantly transformed cells.

Reactivation and the Pathogenesis of Infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The activation of latent herpesviral infection is a critical aspect of the care of the transplant recipient. Reactivation is more common in immunosuppressed hosts, notably in those with depressed T cell immune function. A series of specific stimuli including concomitant infections, fever (tumor necrosis factor-α release), T cell depletion, age, graft rejection, pulse-dosed corticosteroids, radiation, trauma) appear to promote viral replication. There appears to be a linkage between certain major histocompatibility complex (MHC) antigens and the risk for active HSV or EBV infections [20, 21]. The precise mechanisms underlying the activation of virus from latency are poorly understood.

In immunologically normal hosts, most herpesvirus infections are asymptomatic or minimally symptomatic. This feature contributes to the facile spread of infection between hosts. Thus, HSV, CMV, HHV-6 and HHV-7, and EBV are shed from the oral mucosa with few if any visible lesions or symptoms other than mild fever or lymphadenopathy. Individuals with new VZV infections generally present clinically with chickenpox (although the rash may appear after a period of nonspecific symptoms) or with reactivation infection as shingles.

During lytic infection, the order of gene expression is consistent with the life cycle of the virus: [1] immediate-early genes (α genes) require no prior viral protein synthesis and encode proteins that regulate viral gene expression; [2] early genes (β genes) requiring no prior viral DNA synthesis and produce the enzymes important for viral DNA replication and protein phosphorylation [3]; “leaky-late” genes (γ1 genes) are transcribed at the onset of viral DNA synthesis; and [4] true late genes (γ2 genes) produce structural proteins, including the viral glycoproteins and nucleocapsid proteins. Viral genes are transcribed and nucleocapsids are assembled in the nucleus.

Activation of lytic virus replication produces symptomatic disease for some of the herpesviruses, resulting in skin lesions due to HSV or VZV or visceral lesions due to HSV, VZV or CMV (Tables 1 and 2). Other diseases, such as erythema multiforme associated with HSV, are largely due to immune responses to replicating virus—and may be less commonly seen in immunosuppressed transplant recipients. Similarly, the symptoms from EBV-infectious mononucleosis (or similar disease due to CMV) are largely due to the immune response to the infection rather than to direct, lytic destruction of virus-infected cells. In the normal host, the production of transcripts that (e.g.) interfere with presentation of viral antigens on the cell surface or mimic major histocompatibility antigens or anti-inflammatory cytokines, serve to allow a window within which viral replication may occur [15]. EBV and CMV encode interleukin-10 (IL-10) homologues, KSHV encodes an IL-6 homolog, HHV-6 and HHV-8 encode chemokines and CMV, EBV, HHV-6, HHV-7 and KSHV encode chemokine receptor homologs [22]. HSV and CMV also encode proteins that inhibit display of MHC class II molecules and that inhibit the TAP protein required for processing MHC class I molecules. KSHV proteins enhance endocytosis of MHC class I molecules from the cell surface and inhibit NK cells. Multiple viruses produce proteins that inhibit interferon and the cell surface binding of antibody and complement. In the immunocompromised host, viral protective mechanisms are more effective and allow for the rapid spread of infection between cells and higher circulating viral loads. Thus, disseminated shingles and HSV pneumonia reflect the spread of virus beyond the original site of latency in neurons in the absence of immunological control.

Table 2. The epidemiology of human herpesvirus infection
  Estimated seroprevalence (%)
VirusClinical syndromes in transplantationChildrenAdults—United StatesAdults—Developing World
  1. CMV = cytomegalovirus; EBV = Epstein–Barr virus; HHV = human herpesvirus; HSV = herpes simplex virus; KSHV = Kaposi's sarcoma–associated herpesvirus; VZV = varicella-zoster virus.

  2. *No approved assays.

HSV1Cutaneous herpes, gingivostomatitis, keratoconjunctivitis, encephalitis, pneumonitis, genital lesions, esophagitis, hepatitis20–4050–7050–90
HSV2Genital lesions, cutaneous herpes, gingivostomatitis, keratoconjunctivitis, meningitis, encephalitis, pneumonitis, esophagitis, hepatitis0–520–5020–60
VZVShingles (extradermatomal), pneumonitis, disseminated infection, hepatitis, retinitis, meningitis, hemolysis, leukopenia, thrombocytopenia50–7585–9550–80
CMVLymphadenopathy, hepatitis, pneumonitis, cns vasculitis/encephalitis, retinitis, esophagitis, hemolysis, leukopenia, thrombocytopenia10–3040–7040–80
EBV Types 1&2Mononucleosis, posttransplant lymphoproliferative disorders, pneumonitis, hepatitis, encephalitis, hemolysis, leukopenia, thrombocytopenia10–5080–9590–100
HHV6 types A and BRash, fever, encephalitis, pneumonitis, hepatitis, leukopenia, thrombocytopenia80–10060–10060–100
HHV7Encephalitis?, hepatitis?50–8060–10040–100
HHV8/KSHVFever, mononucleosis, skin lesions, encephalitis?<3*3–5*10–50*

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

Most adults in the United States are infected with HSV-1, VZV, EBV and probably HHV-6 and HHV-7 [23, 24]. About half are infected with CMV (Table 2). KSHV is common in certain areas (Mediterranean, South America) [5]. Seropervalence rates for HSV-1, HSV-2, CMV and EBV are higher in developing regions. Activation by depression of cellular immune function and/or T cell depletion may be associated with disseminated and atypical infections. Conversely, few patients suffer graft rejection during active herpesviral infections unless immune suppression is discontinued. Opportunistic superinfection of all types is common, suggesting that immune suppression due to the herpesvirus may be occurring. These have been variably termed ‘indirect effects’ or the cellular and immune effects of viral infection. These include the predilection to opportunistic infections (e.g. Pneumocystis pneumonia and other fungal infections), to graft rejection and to virus-associated malignancies. The genes described above related to protection of the virus from cellular immune responses may play a role in systemic immune suppression, but this remains to be proven.

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

Most herpesvirus infections can be diagnosed in the normal host based on clinical symptoms and signs. Some of the traditional assays remain quite useful including the Tzanck prepration which is a Giemsa-stained smear from the base of fresh vesicles in herpes simplex, chicken pox and shingles lesions. Staining reveals multinucleated giant cells with homogeneous nuclear staining due to viral inclusions, but cannot differentiate between the herpesviruses. Histopathology remains the gold standard for diagnosis of tissue-invasive infection—now often supplemented by immunohistologic stains for viral antigens on tissues or scarpings from lesions for direct fluorescent antibody staining. Lytic replication of herpesviruses produces characteristic intranuclear (CMV, HHV-6) or intracytoplasmic (CMV, HHV-6, HSV, VZV) inclusions in tissues. In the case of EBV, in situ molecular amplification of EBV-encoded small nuclear RNAs (EBERs) is more sensitive than in situ staining for viral DNAs. Latent antigens of EBV can be detected by immunohistochemistry for the EBNA-1, EBNA-2 and LMP-1. Flow cytometry for patients with EBV-associated cellular proliferation may detect monoclonal populations.

Serologic testing reveals only prior exposure but is generally not useful for acute diagnosis in the immunocompromised host. Immunoflourescence-based antigen detection assays such as the shell vial for CMV have largely been replaced by early antigen detection (pp65) in neutrophils or molecular testing.

One of the areas of rapid evolution has been in the field of molecular diagnostic assays. Nucleic acid testing (NAT) has enhanced the sensitivity and rapidity of diagnostic testing, notably in HSV, VZV, EBV, CMV or HHV-6 encephalitis and systemic CMV and EBV infections in transplant recipients. NAT has also revolutionized the management of active infections in terms of measuring the response to antiviral therapy, including reductions in immunosuppression. Serial monitoring of viral infections is most common currently in CMV, EBV or HHV-6 infections. Molecular testing for resistance to antiviral agents has been a great advance in the care of CMV-infected patients. Intralaboratory variability in data from NAT tests makes comparison of data between clinical laboratories less useful. Thus, it is better to follow individual patients with serial assays performed in a single laboratory so that comparisons are valid. Variability may be reduced through use of international viral standards (e.g. for CMV and EBV) for laboratory assay quality assurance.

Asymptomatic shedding of herpesviruses in urine and sputum samples make viral cultures less useful for diagnosis from these sites. In general, positive samples of urine or sputum in the absence of evidence for invasive disease (virus found in tissues or in blood) should be viewed with skepticism. Culture of the herpesviruses has generally been displaced by NAT testing other than for analysis of drug-resistant viruses. With increased knowledge of the genetic sequences of resistance mutations, cultures are less often required.

Treatment and Prevention

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The available antiviral agents have no effect on latent virus and cannot eradicate infection as a result. Thus, one cornerstone of antiviral therapy is the reduction of immunosuppression during acute infection to the degree possible without provoking graft rejection. Increased immunosuppression may be required after the resolution of infection. One of the main limitations to the treatment of herpesvirus infections is that all of the FDA-approved antiviral agents act at the viral DNA polymerase. Foscarnet and cidofovir are active without modification and thus are associated with increased toxicities. Acyclovir and penciclovir require modification by the HSV or VZV thymidine kinase. Ganciclovir is activated by the CMV UL97 protein kinase. Ganciclovir-resistance mutations at UL97 impair the phosphorylation of GCV, presumably by altering substrate recognition.

The prodrugs valacyclovir, valganciclovir and famciclovir are converted to their active forms by intracellular enzymes. Newer agents under investigation may inhibit viral protein kinases (marabavir) or may have additional, novel sites of action (lipid-associated cidofovir). Newer approaches to therapy include the adoptive transfer of syngeneic, cytotoxic T cells stimulated with viral antigens in vitro to attack latently infected cells. The use of hyperimmune human globulin preparations has been studied largely in the prevention and treatment of CMV and VZV infections in transplantation. Activation of latent virus (e.g. using histone deacetylase inhibitors) to lytic infections may eliminate some cells with latent virus and/or allow activity of antiviral agents against reactivated virus. Resistance to antiviral agents is uncommon even in transplantation.

In patients at increased risk for viral reactivation, both prophylaxis and vaccination have been attempted to reduce the frequency or severity of infection. This topic is discussed in detail elsewhere in this supplement by Emery [25-27]. Acyclovir, valacyclovir, valganciclovir and famciclovir all reduce recurrences of HSV and of varicella in immunologically naive patients following exposure to VZV. Ganciclovir and valganciclovir reduce the incidence of CMV disease in transplant recipients. Prevention of infection should be individualized for various immunosuppressive regimens and the patient. Two strategies are commonly used [1]: universal prophylaxis and [2] preemptive therapy (see summary box 2). Live attenuated vaccines are available for VZV to prevent varicella and zoster. Subunit vaccines are under development for HSV, CMV and EBV. These are discussed further by Emery and Khanna.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

The human herpesviruses remain an important challenge in the immunocompromised host. Some aspects of the biology of these pathogens remain to be defined including the mechanisms controlling the development of viral and reactivation from latency. Serology remains a useful marker for latent infection and molecular-based assays have improved the specific diagnosis for infections. The spectrum of antiviral agents remains limited with important toxicities and the growing threat of resistance to antiviral therapies. In the near future, it will be important to refine the terminology to better reflect the biology of infection by ach viral type—from ‘indirect effects’ to the specific mechanisms by which viral infections exert the broad, systemic effects that predispose transplant recipients to opportunistic infections, malignancy and graft injury.

Summary Box 1

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions
Key Concept: Heterologous Immunity

In the transplant recipient, herpesvirus infections, especially CMV, are associated with adverse effects including an increased rate of graft rejection, opportunistic infections and malignancies. In clinical trials, effective prophylaxis is associated with reduced rates of graft rejection and opportunistic infections. Heterologous immunity is the concept used to describe the situation in which immune memory responses to previously encountered pathogens alter subsequent immune responses to unrelated pathogens or to grafts. Some of these effects are attributed to the generation of immunological cross reactivity between viral epitopes and graft and other antigens. The observed effects may be mediated via memory CD8+ cells following viral infection or more broadly by inflammatory mediators such as TNFα, IFNγ. Such virally induced alloreactive memory may create a barrier to transplantation tolerance or induce graft rejection or autoimmunity [28-31]. Such effects have been demonstrated for both CMV and EBV [32]. Further, viral reactivation in the face of elevated frequencies of activated antigen-specific memory T cells may have a variety of undesirable effects including the compression of the T cell repertoire and diminished responses to new antigens. This might result in an increased risk for opportunistic infections [33, 34]. Reactivated or persistent viral infections such as those common for the herpesviruses may generate excessive or chronic cytokine responses with a bias of T cells to effector cells with a lower quality of subsequent memory responses. The nonspecific activation of inflammatory mediators in the course of viral infection may also activate or enhance preexisting innate and adaptive immune responses against the graft. Thus, all limbs of the host immune response may be altered by herpesvirus infection, including adaptive as well as NK cell, neutrophil and macrophage responses, and may contribute to the risk for graft injury and opportunistic infections.

Summary Box 2

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions
Key Concept: Antiviral Prophylaxis

Infection is generally easier to prevent than to treat. Universal prophylaxis involves providing antiviral therapy to all “at-risk” patients beginning at or immediately posttransplant for a defined time period. In preemptive therapy, quantitative assays are used to monitor patients at predefined intervals to detect early disease. Positive assays result in therapy. Preemptive therapy incurs extra costs for monitoring and coordination of outpatient care while reducing the cost of drugs and the inherent toxicities of drug exposure. Thus, prophylaxis with (e.g.) ganciclovir or valganciclovir has the advantage of preventing most infections due to CMV during the period of prophylaxis, but also decreases infections due to HSV, VZV, HHV6, HHV7 and EBV while receiving antiviral therapy. Further, the ‘indirect effects’ or immunological effects of CMV (i.e. increased rates of graft rejection and opportunistic infections) are also reduced by routine, universal prophylaxis. In practice neither strategy is perfect. Breakthrough disease (uncommon) and ganciclovir resistance have been observed in both approaches. Increasingly, “late” disease has been observed after the completion of prophylaxis unless immunosuppression is able to be reduced and immune competence for the virus is demonstrated.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions

Questions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Viral Structure
  5. General Properties and Patterns of Replication
  6. Infection, Host Range and Viral Latency
  7. Reactivation and the Pathogenesis of Infection
  8. Epidemiology
  9. Diagnosis
  10. Treatment and Prevention
  11. Conclusions
  12. Disclosure
  13. Summary Box 1
  14. Summary Box 2
  15. References
  16. Questions
  1. The herpesviruses associated with cellular or immunological effects (“indirect effects”) in the transplant recipient include
    1. Cytomegalovirus
    2. Herpes simplex virus types 1 and 2
    3. Epstein–Barr virus
    4. Varicella zoster virus
    5. All of the above
  2. The presence of herpesvirus DNA in which of the following clinical samples should be taken as evidence of active infection?
    1. Sputum
    2. Blood
    3. Urine
    4. Stool
    5. Bronchoalveolar lavage fluid
  3. Which of the following viruses is NOT associated with pneumonitis in transplant recipients?
    1. Herpes simplex virus type 1
    2. Herpes simplex virus type 2
    3. Varicella zoster virus
    4. Kaposi's sarcoma associated herpesvirus
    5. Cytomegalovirus
  4. Which of the human herpesviruses is NOT associated with skin lesions or rash?
    1. Cytomegalovirus
    2. Herpes simplex virus
    3. Varicella zoster virus
    4. Kaposi's sarcoma associated herpesvirus
    5. Herpes B virus (macaques)