ReviewHerpesviruses and immunity: The art of evasion
Introduction
Over 130 distinct herpesvirus species have so far been identified and, as a group, boast an impressively broad spectrum of hosts. A recent taxonomic clarification of these species (Davison et al., 2009) defined three families within the order Herpesvirales—Herpesviridae, divided into the α-, β-, and γ-herpesvirinae subfamilies and containing herpesviruses that infect mammalian, reptile and avian hosts, Alloherpesviridae, which infect fish and amphibian hosts, and Malacoherpesviridae, with a sole member targeting the invertebrate bivalve mollusk. Herpesviruses are enveloped viruses with a linear double-stranded DNA genome of between 125 and 290 kbp in length (Pellett and Roizman, 2007). Although members of each family are likely to have descended from a common ancestor, little genomic similarity exists between the three families (McGeoch et al., 2006). Nevertheless, all herpesviruses share a number of biological properties including the ability to establish latent infection in their host, during which viral gene expression is minimized. Production of viral progeny during primary infection, or reactivation from the latent state, results in lysis of the infected cell.
In vivo, each herpesvirus is primarily associated with a single host species or narrow host species range. Co-existence over millions of years has compelled the hosts to develop a multi-faceted antiviral immune response. In turn, viruses have become adapted to the challenge of facing the formidable host immune system. Thus, in most situations a balance is achieved whereby herpesvirus infections are largely controlled by the host, though failure to completely eradicate the virus results in infection persisting for life. While most infections are asymptomatic, herpesviruses cause several diseases in both immunocompromised and immunocompotent hosts (Kutok and Wang, 2006, Mocarski et al., 2007, Roizman et al., 2007). Pathological conditions can arise upon primary infection with the virus, upon viral reactivation after a period of latency, or due to the inherent oncogenic potential possessed by certain herpesviruses.
The α-herpesviruses herpes simplex virus (HSV)-1 and -2 are two of the eight herpesviruses known to infect humans (Roizman et al., 2007). Primary infection results in viral entry into sensory nerve ganglia, where latency is established. Periodic reactivation and lytic replication of the virus can result in mucosal lesions, presenting as oral cold sores or genital ulcerative disease for HSV-1 and -2, respectively. Another α-herpesvirus, varicella-zoster virus (VZV) is the causative agent of varicella, or chicken pox, which can occur upon primary infection, and herpes zoster, or shingles, which may arise during reactivation (Cohen et al., 2007). Members of the α-herpesvirus subfamily are also the etiologic agents of several animal diseases with an important impact on agriculture. Equine herpesvirus (EHV)-1 and -4 are endemic in horse populations and can lead to respiratory diseases, abortions and neurological disorders (Patel and Heldens, 2005), while bovine herpesvirus (BoHV)-1 has similar effects in cattle (Yates, 1982). Pseudorabies virus commonly infects pigs causing Aujeszky's disease (Nauwynck, 1997). Chickens are the hosts of the oncogenic α-herpesvirus Marek's disease virus (MDV) (Nair, 2005), which can bring about immunosupression and T cell lymphomas as well as infectious laryngotracheitis virus causing respiratory disease.
The most extensively studied members of the β-herpesvirus subfamily are the cytomegaloviruses, including human (HCMV) and murine cytomegalovirus (MCMV) (Mocarski et al., 2007). HCMV infection is usually subclinical in healthy individuals. However, in immunocompromised hosts, HCMV can cause pathology in multiple organ systems with high mortality rates. HCMV is also a risk factor for congenital birth defects when the mother experiences primary infection during pregnancy.
Murine γ-herpesvirus-68 (MHV-68), Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) are well-characterized lymphotrophic γ-herpesviruses. KSHV and EBV are associated with several malignancies in humans, including primary effusion lymphoma (KSHV) and Burkitt's lymphoma as well as nasopharyngeal carcinoma (EBV) (Kutok and Wang, 2006, Wen and Damania, 2009).
Virus survival at each stage of its life cycle – primary infection, establishment of latency and reactivation to produce new virions – depends on evasion of the host immune response. The fact that herpesviruses persist for life indicates that they have evolved successful strategies to thwart host immunity (Powers et al., 2008, Ressing et al., 2008, Vossen et al., 2002). Here, we review some of the mechanisms employed by herpesviruses to avoid eradication, with a particular focus on viral interference with the MHC class I antigen processing and presentation pathway.
Section snippets
Often outgunned but never outfought: herpesviruses take on the host immune response
To appreciate the elegance of the mechanisms utilized by herpesviruses in avoiding elimination, a prior understanding of the immune response arsenal possessed by their hosts is required. The mammalian immune system senses the presence of herpesvirus particles using a range of pattern-recognition receptors (PRRs), recognizing as ligands essential proteins and nucleic acids that are specific to viruses (Akira et al., 2006). Detection of these pathogen-associated molecular patterns then triggers
MHC class I antigen processing and presentation pathways
The production of prospective ligands for CD8+ T cell receptors begins in the cytosol of all nucleated cells. Proteins, or defective ribosomal products (DRiPs), are degraded by the multi-subunit proteasome complex in a ubiquitin-dependent manner to short peptide fragments (Hershko and Ciechanover, 1998, Voges et al., 1999). The make-up of this large cylindrical complex becomes altered during an immune response. Stimulation of cells with IFN-γ results in the formation of the immunoproteasome,
Closing time: α- and γ-herpesviruses shut down host protein production
Synthesis of the antigen presentation pathway components offers the first point of interference by herpesviruses. Upon infecting a host cell, HSV immediately sets about crippling cell function by shutting down host protein production. This is achieved by delivering the virion-associated UL41 gene product, named virion host shutoff (vhs) protein, directly to the cytoplasm (Smiley, 2004). vhs and its homologues within the α-herpesvirus subfamily, display sequence similarity with a family of
Stopping it at source: viral inhibition of proteasome activity
Several herpesviruses can hamper the generation of peptides for presentation to cytotoxic T cells by inhibiting proteasome activity. This can be achieved by targeting the synthesis and assembly of the immunoproteasome and the regulatory PA28αβ protein. MCMV-infected cells experience a block in IFN-γ-mediated immunoproteasome formation, brought about at the transcriptional level by M27, an inhibitor of IFN-γ signalling (Khan et al., 2004). IFN-γ-induced PA28αβ synthesis was also found to be
Trapping TAP: viral inhibition of peptide transport
TAP-mediated transport of peptides to the ER lumen is a common target for herpesvirus proteins that inhibit the MHC class I loading pathway. So far, TAP-inhibitors have been identified in HSV (Fruh et al., 1995, Hill et al., 1995), BoHV-1 (Koppers-Lalic et al., 2005), EHV-1 and -4, PRV (Koppers-Lalic et al., 2008), HCMV (Ahn et al., 1997, Hengel et al., 1997, Lehner et al., 1997), EBV (Hislop et al., 2007); in Rhesus CMV (RhCMV), which infects Rhesus Old World primates (Pande et al., 2005); and
ERADicating MHC class I molecules
In addition to antagonizing proteasome-mediated peptide generation and TAP transport, herpesviruses can also co-opt and accelerate cellular processes to achieve inhibition of MHC class I antigen presentation. ER-associated degradation (ERAD) is part of a quality control system, in which misfolded nascent glycoproteins are dislocated from the ER lumen to the cytosol, where the ubiquitin-proteasome system mediates their destruction (Vembar and Brodsky, 2008). A mechanistic understanding of ERAD
Holding on for dear life: virus-mediated intracellular retention of MHC class I molecules
In addition to US2 and US11, the HCMV-encoded US3 protein also hinders MHC class I-mediated peptide presentation (Ahn et al., 1996, Jones et al., 1996). The ER-resident type I transmembrane protein interacts with tapasin and affects only tapasin-dependent alleles (Park et al., 2004). This implies that US3 prevents tapasin-mediated peptide-loading, which results in unstable MHC class I molecules that are transported out of the ER and degraded. US3 also interacts directly with tapasin-dependent
Step back inside: virus-mediated endocytosis of MHC class I molecules
Even after MHC class I molecules depart the ER with their peptide cargo and successfully negotiate the secretory pathway, the antigen presentation pathway can still be disrupted by herpesviral immunoevasins. KSHV expresses the MARCH E3 ubiquitin ligases kK3 and kK5 (also known as MIR1 and MIR2, respectively) that display a high degree of homology to MHV-68 mK3 (Coscoy, 2007, Wang et al., 2008). However, they act further downstream than their murine γ-herpesvirus counterpart, orchestrating the
A license to silence: miRNAs as viral immunoevasins
Recently, it has emerged that the subversive capabilities of herpesviruses are conferred not only by viral proteins but also by virus-encoded micro-RNAs (miRNAs) (Cullen, 2009, Nair and Zavolan, 2006). Their non-immunogenicity and relatively small occupation of viral genome coding capacity makes miRNAs a shrewd choice as immunoevasive molecules. miRNAs are processed from primary miRNA transcripts by the sequential action of the nuclear and cytoplasmic endoribonucleases Drosha and Dicer,
Conclusion
Large DNA viruses dedicate a substantial amount of genome coding capacity to blocking the host immune response at many levels. This is a testament both to the significance of the individual antiviral response mechanisms targeted, and to the critical importance of immune evasion in the perpetuation of viral infection. Here, we have aimed to give an overview of the methods used by α-, β, and γ-herpesviruses in escaping immune elimination, in particular by thwarting cell-mediated immunity at
Conflict of interest
The authors declare that no conflicts of interest exist.
Acknowledgement
We thank the Dutch Cancer Society (grant UL 2005-3259) and the Macropa Foundation, Leiden, for financial support.
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