Herpes Simplex Virus

Herpes Simplex Virus

Herpes Simplex Virus A Cliffe* University of North Carolina at Chapel Hill, Chapel Hill, NC, USA L Chang*,y Nikon Instruments, Melville, NY, USA R Col...

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Herpes Simplex Virus A Cliffe* University of North Carolina at Chapel Hill, Chapel Hill, NC, USA L Chang*,y Nikon Instruments, Melville, NY, USA R Colgrove, Mount Auburn Hospital, Cambridge, MA, USA DM Knipe, Harvard Medical School, Boston, MA, USA Ó 2014 Elsevier Inc. All rights reserved.

Glossary Anterograde transport The direction of axonal transport from the cell body to the synapses. By contrast, retrograde axonal transport is from the synapses to the cell body. Apoptosis An active form of cell death that occurs during development and in response to pathogenic stimuli, including viral infection. Cell death ultimately occurs due to activation of cellular caspases and results in specific morphological changes. Cell fragments called apoptotic bodies are produced, which are engulfed by phagocytic cells. Euchromatin Decondensed regions of chromatin that are accessible to transcription factors and represent regions of DNA undergoing active gene expression. Heterochromatin Highly condensed regions of chromatin that are inaccessible to transcription factors and therefore transcriptionally silent.

Introduction Herpes simplex virus (HSV) is a large DNA virus that commonly infects humans. There are two species, herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2), which have historically been associated with oral herpes and genital herpes, respectively. They infect mucosal tissue acutely and spread and establish a latent infection in sensory neurons. At later times they reactivate to cause recurrent infection. They are members of the order Herpesvirales, the family Herpesviridae, the subfamily Alphaherpesvirinae, and the genus Simplexvirus. HSV shares a common virion structure and replication with the other herpes viruses, but they have unique mechanisms of latent infection.

Virion Structure The HSV virion is a spherical particle with an average diameter of 186 nm with spikes that extend the overall diameter to 225 nm (Grunewald et al., 2003; Figure 1 and Movie 1). The outermost layer of the virion is a lipid bilayer envelope decorated with spikes made of glycoproteins (Roizman and Furlong, 1974). Beneath this layer is a relatively unstructured proteinaceous layer called the tegument, which in turn surrounds an icosahedral nucleocapsid. The nucleocapsid sits

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Contributed equally. Corresponding author.

Reference Module in Biomedical Research, 3rd edition

Immunocompromised An individual whose immune system is compromised in some way and therefore lacks the ability to mount a normal immune response to infection. Interferon A family of secreted glycoproteins made in response to pathogen infection or tumor cells. Interferons allow communication between cells to inhibit viral replication or clearance of tumor cells. Latent infection A quiescent period of infection when most or all of the viral lytic genes are silenced, and the progeny virus is not produced. Lytic infection A type of infection in which viral lytic genes are expressed and the virus actively undergoes replication and makes progeny virions, ultimately resulting in destruction of the cell. This is also referred to as a productive infection.

at an eccentric position in the virion with one end closer to the envelope than the other (Grunewald et al., 2003). Inside the nucleocapsid resides the core, a double-stranded DNA genome, approximately 150 Kbp in length, arranged as a toroid (Furlong et al., 1972) or spool (Zhou et al., 1999) in a liquid crystalline state (Booy et al., 1991). Studies involving purified HSV-1 virions suggest there are more than 30 distinct proteins that constitute these particles (Heine et al., 1974; Spear and Roizman, 1972). Up to 13 of these are found embedded in the lipid bilayer on the surface of the virion. The majority of these surface proteins are glycosylated. Only gB, gD, and gH-gL, all involved in viral entry, are depicted in Movie 1 and Figure 1 for simplicity (shown as green, yellow, and orange spikes, respectively, on the viral membrane). The tegument contains more than 18 distinct proteins, including VP16, a virion transactivator protein, the virion host shutoff (VHS) protein, and VP1-2, which is involved in releasing the DNA at the nuclear pore during viral entry (reviewed in Vittone et al., 2005). The nucleocapsid exhibits a T ¼ 16 icosahedral symmetry and consists of 162 capsomeres which include 140 hexons (light blue), 11 pentons (red), and one portal (dark blue; Movie 1 and Figure 1). The hexons and pentons are made of six and five copies of the major capsid protein VP5, respectively. On top of each hexon is a ring of six VP26 proteins (Zhou et al., 1995). Minor capsid proteins UL25/17, which surround pentons, are thought to serve as potential tegument binding sites (shown in yellow in Movie 1 and Figure 1; Trus et al., 2007). Linking adjacent capsomeres are triplexes (green), each made

http://dx.doi.org/10.1016/B978-0-12-801238-3.00080-5

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Figure 1 HSV structure (see also Movie 1). The outermost layer is a lipid envelope studded with glycoprotein spikes (gB trimer in green; gH-L heterodimer in orange; gD dimer in yellow). Beneath the envelope is a proteinaceous tegument layer followed by the capsid. The capsid sits at an eccentric position within the virion with one vertex closer to the envelope than the other. Hexons are shown in light blue, pentons in red, UL25/17 in yellow, and triplexes in green. The portal, thought to serve as an entryway for DNA during packaging is shown at the bottom vertex of the capsid (dark blue). The DNA core, depicted as a spool, resides within the capsid. The model was compiled and modified from EM Database (EMDB) image 1354 (capsid), EMDB 5260 (portal), PDB 3M1C (gH-L), PDB 2GUM (gB), and PDB 2C36 (gD). Copyright, Lynne Chang and David Knipe.

of one VP19C molecule and two VP23 molecules (Zhou et al., 2000). A dodecamer of the UL6 protein is thought to form a portal (shown in dark blue at the bottom of the capsid in Movie 1 and Figure 1; Trus et al., 2004) through which the viral DNA is packaged and released. In addition to proteins, virions also contain transcripts of cellular and viral origin (Sciortino et al., 2001), mostly likely within the tegument layer (Sciortino et al., 2002), and lipids in the viral membrane. The envelope lipids are assumed to be derived from the infected host (Spear and Roizman, 1967) and are most likely acquired from cytoplasmic rather than nuclear membranes (van Genderen et al., 1994).

Viral Replication Overview HSV undergoes productive replication in diverse cell types, including fibroblasts, epithelial cells, lymphocytes, and neurons, ultimately resulting in the production of progeny virions and death of the host cell. At the same time, HSV must overcome host defense mechanisms that would otherwise restrict its replication. Replication initiates with fusion of the viral envelope with the cellular membrane and delivery of the capsid and tegument proteins into the cytoplasm. Viral gene expression takes place in a temporal cascade in the nucleus. This sequential pattern of viral gene expression allows for classification of HSV genes into three broad categories based on

when they are expressed. The categories consist of immediate early (IE) or a genes, the early (E) or b genes, and the late (L) or g genes (Figure 2). The a genes are expressed independently of de novo viral protein synthesis. Expression of the b genes depends on expression of a proteins. b gene products, in turn, are required for viral DNA replication. The g genes are transcribed last with their transcription efficiency depending to varying degrees on viral DNA replication. Many of the late gene products are structural proteins that are involved in the assembly of progeny virions. Following late gene expression, viral capsids are assembled and filled with viral DNA. Nucleocapsids then bud through the inner nuclear membrane or exit through the nuclear pore. There are competing theories regarding the ultimate site of tegument and envelope acquisition, the details of which will be discussed further in a later section.

Cell Entry Entry of HSV into cells can be broken down into two steps: (1) Binding of viral glycoproteins to cellular receptors, followed by (2) fusion of the viral envelope with the plasma or endocytic membrane (Figure 2; reviewed in Connolly et al., 2011; Campadelli-Fiume et al., 2011). In the first step, the interaction of the gC and gB surface glycoproteins with glycosaminoglycans (GAGs) serves to tether the virus to the cell surface. This step, while not critical, enhances the efficiency of virus entry. Irrespective of the method of entry used by the virus (direct

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Figure 2 Replication cycle of HSV. HSV binds to the plasma membrane of the cell and enters either through (1a) fusion or (1b) endocytosis. The tegument and capsid are released into the cytoplasm where upon (2) the capsid is transported the nucleus and the viral DNA is released through the nuclear pore complex into the nucleoplasm. (3) Tegument proteins VHS causes destruction of cellular mRNA in the cytoplasm. (4) VP16, another tegument protein localizes to the nucleus. (5) Upon entering the nucleus, viral DNA circularizes and recruits RNA pol II to begin (6) transcription of the alpha genes. Transcription of these genes is stimulated by VP16. (7) Products of alpha gene expression transactivate expression of beta genes. (8) Beta gene products, in turn, initiate viral DNA replication which in turn (9) stimulates gamma gene expression. (10) Products of this last class of genes are involved in assembling the capsid and modifying membranes for virion formation. (11) Capsids are filled with progeny DNA and bud through the inner nuclear membrane. (12) The virion is transported through the cytoplasm and exits the cell as an infectious viral particle. Copyright, Lynne Chang and David Knipe.

fusion or endocytosis), the next step requires the interaction of virion glycoprotein D (gD) with one of its receptors. gD is capable of binding three cellular receptors that are distributed on a variety of cell and tissue types: a member of the tumor necrosis receptor family known as herpes virus entry mediator (HVEM), nectin 1 and 2, which are cell surface adhesion molecules and members of the immunoglobulin superfamily, and a form of 3-O-sulfated heparansulfate (Montgomery et al., 1996; Geraghty et al., 1998; Shukla et al., 1999). Receptor binding of gD results in a conformational change to itself and to additional viral glycoproteins, namely gB and the gH-gL heterodimer (Connolly et al., 2011), which ultimately leads to fusion of the envelope with cellular membranes and delivery of the viral capsid and tegument proteins into the cytoplasm. Once inside the cell, a number of tegument proteins dissociate to form the nucleocapsid and remain in the cytoplasm, while others, such as the lytic transactivator VP16, translocate to the nucleus (Figure 2). The capsid is transported along microtubules to the nuclear pore, where the viral DNA is released into the nucleus.

IE Gene Expression Once inside the nucleus, the viral DNA localizes to the nuclear lamina, circularizes (Strang and Stow, 2005) and associates with

cellular histones (Herrera and Triezenberg, 2004; Kent et al., 2004; Cliffe and Knipe, 2008). The viral tegument protein, VP16, plays a key role in the initiation of a gene expression. VP16 interacts with the cellular proteins, HCF-1 and Oct-1, to form the activator complex (reviewed in Kristie et al., 2010). One key function of the activator complex is the recruitment of additional cellular proteins that reduce heterochromatin and promote euchromatin association with the a gene promoters (Narayanan et al., 2007; Liang et al., 2009). VP16 also promotes the formation of the RNA polymerase II preinitiation complex and recruits cellular proteins that remodel chromatin during transcription (Neely et al., 1999; Herrera and Triezenberg, 2004). Viral proteins are preferentially translated over cellular proteins during infection due to the activity of the viral tegument protein VHS. VHS stays in the cytoplasm and destabilizes host mRNA, thus ceasing host protein synthesis and increasing the preferential translation of viral proteins (Figure 2). Expression of a genes triggers the subsequent cascade of b and g gene expression and aids in evasion of cellular responses to infection (Figure 2). One of the a gene products, infected cell protein (ICP) 4, is essential for all post-a gene expression (DeLuca et al., 1985; Dixon and Schaffer, 1980; Preston, 1979; Watson and Clements, 1980), which is most likely due to its ability to enhance the recruitment of both transcription factors and RNA polymerase II to b and g gene promoters

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(Sampath and Deluca, 2008). ICP0, another a gene product, is a broad/nonspecific transactivator, which stimulates the expression of all three temporal classes of viral genes (Cai and Schaffer, 1992; Chen and Silverstein, 1992), although it does not bind DNA directly. ICP0 functions to remodel the viral chromatin to promote euchromatin formation (Cliffe and Knipe, 2008; Hancock et al., 2010) and degrades proteins involved in intrinsic resistance and innate immune responses (see below). ICP27 is required for g and some b gene transcription as well as multiple other functions including RNA export and translation. ICP22 and US1.5 are also believed to stimulate g gene expression. ICP47 is involved in immune evasion.

E Gene Expression Early proteins or b gene products include those that are involved in viral DNA replication. These include the ssDNA-binding protein (ICP8), origin binding protein (UL9), a two-subunit DNA polymerase (UL30 and UL42), and a helicase–primase complex (UL5, UL8, and UL52). Thus, the expression of this temporal class of genes triggers the onset of viral DNA replication (Figure 2). Certain b gene products, such as ICP8, are also involved in downregulating a gene expression.

DNA Replication Viral DNA replication initiates at one or more of the viral origins of replication, and initially follows a bidirectional theta-type replication, resulting in the amplification of circular molecules (Figure 3). At later times, replication of the viral DNA switches to an origin independent mechanism of replication; either simple rolling-circle and/or recombination based replication (Figure 3). Replication results in the production of concatemers that consist of tandem repeats of the viral genome, which are then cleaved into monomers for packaging within the capsid. Evidence in favor of the rolling-circle DNA replication stems from studies of infected cell replication intermediates and in vitro reconstitution experiments. However, the presence of branched DNA structures in infected cells also argues in favor of recombination based DNA replication. Cellular proteins involved in DNA repair/recombination, including WRN, ATRIP, and MSH2 (Taylor and Knipe, 2004; Mohni et al., 2013, 2011), are also recruited to sites of viral DNA replication, and mutation or depletion of a number of these proteins has been found to reduce HSV replication (Taylor and Knipe, 2004; Mohni et al., 2011, 2013), although whether they act at the stage of DNA replication is not clear. DNA replication takes place within viral-induced intranuclear structures called replication compartments (RCs; Figures 2 and 4). These compartments result in the formation of basophilic nuclear inclusion bodies that are diagnostic of herpes virus infection. RCs develop from small prereplicative foci. As DNA replication proceeds, these structures grow larger in size, move, and coalesce to form larger structures (Taylor et al., 2003; Chang et al., 2011; Figure 5 and Movie 2). Movement of RCs has been demonstrated to include active transport mechanisms involving nuclear actin, myosin, and ongoing transcription (Chang et al., 2011). Replication compartments are also the site of late gene expression and viral

Figure 3 Viral DNA replication. (1) Once the viral DNA enters the nucleus, it circularizes. (2) UL9 binds to the origin and begins to unwind the DNA. ICP8 binds to exposed single stranded DNA regions. (3) ICP8 recruits the remaining viral DNA replication proteins to the replication forks and (4) theta replication ensues. (5) After initial rounds of theta replication, replication switches to rolling circle. The mechanism of this switch is unknown. UL9 is not required for rolling-circle replication. (6) Rolling-circle replication produces concatemers of progeny DNA which are then cleaved into monomers during encapsidation. Copyright, Lynne Chang and David Knipe.

capsid assembly. Along with viral proteins, a number of cellular proteins, including those involved in DNA replication (e.g., DNA ligase, topoisomerase II), chromatin remodeling (Brg1 and SNF2h), and DNA repair (as mentioned above), are also recruited into replication compartments.

Late Gene Expression Late gene transcription is stimulated by viral DNA replication (Honess and Watson, 1974; Figure 2), largely due to increased transcription (Godowski and Knipe, 1986). However, this stimulation has also shown to be mediated in part by a cis-acting effect (Mavromara-Nazos and Roizman, 1987), although the

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Figure 4 HSV infection results in the formation of intranuclear structures called replication compartments. Image shows an epithelial cell infected with HSV-1 for 8 h and stained for the viral ssDNA-binding protein ICP8. Phase contrast imaging reveals the marked reorganization of the nuclear interior with the viral replication compartment occupying a large portion of the nucleoplasm. Copyright, Lynne Chang and David Knipe.

Figure 5 Replication compartments begin as small intranuclear structures which grow in size as replication proceeds. These structures move and ultimate coalesce to form larger structures. Cells were stained for the viral ssDNA-binding protein ICP8 as a marker for replication compartments (see also Movie 2). Copyright, Lynne Chang and David Knipe.

exact mechanism is unclear. Late gene expression is also enhanced by the presence of products of genes expressed earlier in the cascade, including ICP4, ICP22, ICP27, and ICP8. ICP4 has been shown to promote the assembly of preinitiation complexes on the promoter of the late gene gC (Zabierowski and DeLuca, 2004). Interaction between ICP27 and ICP8 is hypothesized to recruit Pol II to viral progeny DNA (Olesky et al., 2005) and further interactions with ICP4 potentially focusing the recruitment to late gene promoters. ICP22 appears to mediate g gene expression by multiple mechanisms: modification of the phosphorylation state of RNA pol II and its activity level (Long et al., 1999; Rice et al., 1995; Fraser and Rice, 2007; Durand and Roizman, 2008); the recruitment of factors that enables transcription of newly synthesized concatemeric DNA (Advani et al., 2000, 2003, 2001); and by promoting the formation of foci adjacent to RCs that contain chaperone proteins and proteasomal factors that may affect late gene transcription in RCs (Bastian et al., 2010).

Viral RNA Export Cellular RNA export from the nucleus is traditionally thought to be tightly coordinated with RNA splicing. However, HSV infection shuts down RNA splicing. This raises the question of

how viral RNA is exported from the nucleus to the cytoplasm. ICP27, among its multiple putative roles, has been proposed to act as a nuclear export factor, promoting the cytoplasmic accumulation of certain viral transcripts such as the long UL24 gene transcript (Pearson et al., 2004; Johnson and Sandri-Goldin, 2009). In addition, there is evidence suggesting the formation of new export structures inside the infected nucleus. RCs have been shown to move and coalesce on surfaces of nuclear speckle bodies (Chang et al., 2011). This coalescence is thought to bridge transcriptionally active RCs with speckles to form structures that enhance the export of viral late transcripts (Chang et al., 2011).

Translation As with DNA replication and transcription, HSV must rely on host translation machinery to synthesize viral proteins. To favor the translation of its own proteins over cellular proteins, HSV has evolved several strategies. These include decreasing the supply of cellular transcripts, counteracting host innate responses, stimulating the activity of translational machinery, and degrading cellular proteins. Viral tegument protein VHS induces the degradation of preexisting host mRNAs (Read and Frenkel, 1983; Figure 2). HSV infection also stimulates the activity of the cellular cap-dependent translational machinery

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and enhances viral protein synthesis by mechanisms mediated in part by ICP0, ICP6 (Desai et al., 1993; Walsh and Mohr, 2006, 2004), and US3 (Chuluunbaatar et al., 2010). ICP27 has also been shown to enhance translation of late mRNAs (Ellison et al., 2005; Fontaine-Rodriguez and Knipe, 2008) by interacting with host translation factors (Fontaine-Rodriguez et al., 2004; Larralde et al., 2006) but the mechanism is yet unclear. ICP0 has also been suggested to affect protein synthesis and accumulation via multiple mechanisms including interaction with the elongation factor 1d (Kawaguchi et al., 1997) and ubiquitin ligases (Liang et al., 2005; Boutell et al., 2002; Hagglund et al., 2002).

Capsid Assembly Many of the late gene products are capsid proteins that localize to the nucleus where capsid assembly occurs. First, empty shells are assembled. These shells contain an internal scaffolding which is lost following insertion or encapsidation of viral DNA. Studies have shown the presence of three types of capsids, called A-, B-, and C-capsids in infected cell nuclear extracts (Gibson and Roizman, 1972). All three types are w120 nm in diameter and contain an outer shell consisting of hexons and pentons made of VP5 as well as triplex structures comprised of VP19C and VP23. C-capsids contain viral DNA and capsid vertex-specific components made of a heterodimer of UL25 and UL17 (Cockrell et al., 2011; Toropova et al., 2011; Figure 1 and Movie 1). C-capsids acquire a tegument layer and envelope to mature into infectious virions (Figure 1 and Movie 1). B-capsids contain the scaffolding proteins VP22a and VP21, and a viral protease VP24. Upon encapsidation of DNA, the scaffolding protein is removed to form C-capsids. A-capsids do

not contain DNA nor scaffolding proteins and are thought to be abortive products of failed encapsidation attempts. Assembly of capsids takes place at early times of infection within replication compartments at sites near viral DNA replication (Church and Wilson, 1997; de Bruyn Kops et al., 1998). At later times, in certain cell types, capsids assemble in nuclear structures called ‘assemblons’ (Nalwanga et al., 1996; Ward et al., 1996). Encapsidation of viral DNA most likely occurs in replication compartments. Terminal components of concatemeric viral DNA molecules are fed into capsids in an energy-dependent process (Dasgupta and Wilson, 1999) through an entry portal made of 12 UL6 proteins (Figure 1 and Movie 1). As viral DNA is fed into the capsid, scaffolding proteins are thought to be displaced. Cleavage of the DNA concatemer into unit length molecules, which is site-specific (Mocarski and Roizman, 1982), is thought to occur upon encapsidation of a length of DNA that fills the capsid. Encapsidation involves at least seven viral gene products but the exact mechanism remains to be elucidated (Conway and Homa, 2011).

Viral Egress Once encapsidation occurs, the nucleocapsid must exit the nucleus, acquire a tegument layer and envelope to become an infectious particle. There are three proposed models for the pathway of HSV egress (Roizman et al., 2007): the dual envelopment model (Skepper et al., 2001), the lumenal model (Johnson and Spear, 1982), and the nuclear pore model (Wild et al., 2005; Figure 6). The dual envelopment model is thought to be the most substantiated of the three. In this model, the

Figure 6 HSV egress models. The three major models for egress are shown. (I) In the lumenal model, the nucleocapsid buds through the inner nuclear membrane and again through the outer nuclear membrane to obtain a second envelope. The virion is then directly transported to the plasma membrane, where upon the outer envelope fuses and the virion, wrapped in inner nuclear membrane lipids, is released into the extracellular matrix. (II) In the dual envelopment model, the virion buds into the perinuclear space and then fuses with the outer nuclear membrane, losing its nuclear lipids. Second envelopment occurs when the nucleocapsid buds into a cytoplasmic membrane such as the Golgi and multivesicular bodies. The mature virion is released into the extracellular matrix when the vesicle fuses with the plasma membrane. (III) In the nuclear pore model, the nucleocapsid travels through an enlarged nuclear pore complex, bypassing the nuclear membranes. Once in the cytoplasm the nucleocapsid buds into cytoplasmic membranes and follows a similar pathway as the dual envelopment model to exit the cell. Copyright, Lynne Chang and David Knipe.

Herpes Simplex Virus mature nucleocapsid first buds through the inner nuclear membrane (Figure 6). This first step is aided by dispersal of the marginated host chromatin (Simpson-Holley et al., 2004) and disruption of the nuclear lamina (Reynolds et al., 2004; Simpson-Holley et al., 2004) mediated by the nuclear egress complex composed of viral UL31 and UL34 proteins (Chang et al., 1997; Roller et al., 2000). The enveloped particle then fuses with the outer nuclear membrane to release the capsid and tegument into the cytoplasm. Secondary envelopment occurs when the tegument-coated capsids buds into cytoplasmic membranes such as the Golgi, the trans-Golgi network, or endosomes. Multivesicular bodies may also be sites of budding as studies have shown a requirement for MVB machinery for viral assembly or egress (Calistri et al., 2007; Crump et al., 2007). Finally, these enveloped virions inside cytoplasmic vesicles are transported to the plasma membrane via normal exocytosis mechanism. Upon fusion of the vesicle and plasma membranes, the virions are released into the extracellular membrane (Figure 6). In the lumenal model, the enveloped virion inside the perinuclear space acquires a second envelope from the outer nuclear membrane, which ultimately fuses directly with the plasma membrane (Figure 6). However, studies showing that the envelope lipids of extracellular virions are more similar to cytoplasmic rather than nuclear membranes disagree with this second model. In the nuclear pore model, nucleocapsids exit through enlarged nuclear pores and bud through cytoplasmic membranes (Figure 6). However, there are conflicting reports regarding the enlargement of nuclear pores and the interaction between capsids and nuclear pore complexes have yet to be determined.

HSV Takes Control of the Host Cell In an effort to limit viral replication in both infected and neighboring cells, the host has evolved multiple mechanisms to sense HSV infection and restrict its replication. In turn, HSV has evolved elaborate strategies to overcome cellular antiviral defense mechanisms. Initial binding and infection by HSV results in the immediate upregulation of distinct classes of cellular mRNAs, some of which may be beneficial to viral infection (e.g., those encoding transcription factors and antiapoptotic proteins), and some that may be detrimental (e.g., stress response mRNAs which act to limit HSV replication (Patel et al., 1998; Amici et al., 2001; Taddeo et al., 2002; MacLeod and Minson, 2010). To prevent translation of the proteins that would otherwise be detrimental to HSV replication, the viral tegument protein delivered into the cell immediately upon infection, VHS, induces rapid shutoff of host cell protein synthesis, disruption of preexisting polyribosomes, and degradation of host mRNAs (reviewed in Taddeo et al., 2002; Smiley, 2004). The inhibition of cellular protein synthesis also ensures the availability of the translational apparatus for the preferential synthesis of viral polypeptides. Following the onset of HSV gene expression, the a protein, ICP27, also contributes to the shutoff of host protein synthesis by suppressing the splicing of cellular pre-mRNAs (Hardwicke and Sandri-Goldin, 1994; Hardy and SandriGoldin, 1994).

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Another first line of defense against virus infection is intrinsic resistance so called because it involves proteins that are constitutively expressed and function to directly restrict viral replication in individual cells. Proteins mediating intrinsic defense are also most likely inactivated during viral infection. Factors that mediate resistance to HSV replication include promyelocytic leukemia (PML) nuclear bodies (also known as ND10s), which are discrete nuclear foci containing proteins involved in multiple cellular pathways, including chromatin assembly, transcriptional repression, DNA damage, and protein stability (Boutell and Everett, 2013). PML bodies migrate to incoming HSV genomes following infection (Everett and Murray, 2005) to result in an environment that is repressive to viral replication (Glass and Everett, 2013; Lukashchuk and Everett, 2010; Everett et al., 2008, 2006; Jurak et al., 2012). Cellular ubiquitin ligases involved in the DNA damage response are also recruited to incoming genomes independently of PML bodies, including RNF8 and RNF168, which in turn recruit 53BP1 (Lilley et al., 2011). Sites of cellular DNA damage are associated with transcriptional repression (Shanbhag et al., 2010); therefore, it is possible that the recruitment of DNA damage proteins to incoming genome also inhibits HSV transcription. The a protein, ICP0 plays a significant role in inactivating cellular intrinsic resistance by degrading components of PML bodies (Muller and Dejean, 1999); (Chelbi-Alix and de The, 1999; Everett et al., 1998; Jurak et al., 2012), along with RNF8 and RNF168 (Lilley et al., 2011). Furthermore, the absence of components of PML bodies, RNF8, or RNF168 allows for increased replication of ICP0 null-viruses (Glass and Everett, 2013; Lukashchuk and Everett, 2010; Everett et al., 2008, 2006; Jurak et al., 2012; Lilley et al., 2011). Therefore, both PML bodies and certain DNA repair proteins can be categorized as components of the intrinsic resistance to HSV that are disrupted upon infection. The induction of programed cell death is also a form of innate immune response against viral infection. By essentially committing suicide before the virus completes its replication cycle, the cell limits the spread to neighboring cells. Both apoptosis and programed necrosis (necroptosis) have been implicated in protection against viral replication (Labbé and Saleh, 2008; Upton et al., 2010). The trigger for programed cell death upon HSV infection is not known. However, infection with recombinant viruses lacking ICP4 and US3 has been found to trigger both apoptosis and/or necroptosis in different cell types (Galvan et al., 1999; Peri et al., 2011). Viral proteins implicated in inhibiting apoptosis include gD (Zhou et al., 2000), gJ (Jerome et al., 2001), and US3 (Hagglund et al., 2002; Benetti et al., 2003; Wang et al., 2011). Like apoptosis, another process hypothesized to limit viral replication is autophagy; a catabolic process required for turnover of cellular components and a survival mechanism during starvation, and in the case of HSV is important in controlling neuronal replication (Yordy et al., 2012). HSV encodes a virulence factor, ICP34.5, which inhibits autophagy and enhances replication in neurons (Chou et al., 1990; Bolovan et al., 1994; Orvedahl et al., 2007). For efficient expression of viral proteins, HSV has two mechanisms to prevent the shutdown of protein synthesis meditated by activation of protein kinase R (PKR). PKR is activated by both type I interferon (IFN) and dsRNA that is produced at late times in infection as a result of synthesis of

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complementary transcripts. Activated PKR phosphorylates and inactivates the a subunit of translation elongation factor eIF-2 (eIF-2a). HSV encodes two proteins that thwart PKR activity: ICP34.5, which binds protein phosphatase 1a and redirects it to dephosphorylate eIF-2a (Chou and Roizman, 1990; Chou et al., 1995; He et al., 1997), and US11, which binds to PKR and prevents its subsequent activation (Roller et al., 1996; Cassady et al., 1998; Poppers et al., 2000; Giraud et al., 2004). Key to reducing HSV replication is the initiation of the innate immune response by the production of type I IFN. The first step in the IFN pathway involves recognition of viral infection. Cellular receptors involved in the recognition of HSV include members of the Toll-like receptors (TLRs) specifically TRL2, TL9, and TLR3 (Kurt-Jones et al., 2004; Sato et al., 2006; Rasmussen et al., 2009; Welner et al., 2008; Sorensen et al., 2008; Leoni et al., 2012; Zhang et al., 2007; Lafaille et al., 2012), the IFN-inducible (IFI)16 (Unterholzner et al., 2010; Orzalli et al., 2012), avb3-integrin (Gianni et al., 2012), and RIG-I (Rasmussen et al., 2009). Upon ligation, downstream signaling pathways result in the activation of transcription factors, including IRF-3 that binds the IFNb promoter to stimulate transcription. Secreted IFNb then binds to its receptor at the cell surface and signals via the Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) pathway, resulting in the transcription of antiviral interferon-stimulated genes (ISGs), along with IFNa, which further augments ISG expression. The viral a protein ICP0 impedes innate signaling responses by reducing the levels of important signaling molecules. For example, ICP0 sequesters IRF-3 away from the IFN promoter and accelerates its degradation (Melroe et al., 2007). In human fibroblasts, nuclear IFI16 is required for IRF-3 activation in response to HSV infection; ICP0 causes intranuclear relocalization and degradation of IFI16 (Orzalli et al., 2012). HSV can also restrict the JAK/STAT signaling pathway to prevent the transcription of ISGs (Eisemann et al., 2007; Johnson et al., 2008; Johnson and Knipe, 2010). However, despite the ability of HSV to modulate the innate signaling pathway, evidence from animal models demonstrate the crucial role of components of the innate signaling response in clearance of acute HSV infection (Leib et al., 1999; Lima et al., 2010; Halford et al., 1997; Chee et al., 2003; Peng et al., 2007; Menachery et al., 2010).

Figure 7 Viral life cycle in the host. (a) During primary infection, HSV enters epithelial cells and undergoes productive replication to produce progeny virus and the infection spreads through the tissue. HSV enters innervating nerve cells and travels via retrograde transport toward the sensory ganglia to establish latent infection in the nucleus of the neuron (b). The viral DNA is circularized and maintained as chromatin in the latent nucleus (c). During reactivation, the virus undergoes limited replication inside the nucleus and travels in an anterograde fashion toward axonal termini where they are released to infect surrounding epithelial tissue, thus beginning another round of productive replication. Copyright, Lynne Chang and David Knipe.

Latent Infection In contrast to a lytic infection as described above, HSV undergoes a latent infection of sensory neurons, in which the lytic proteins are not expressed to detectible levels and the infected cell survives (reviewed in Knipe and Cliffe, 2008). In this way, HSV persist for the lifetime of the individual. HSV enters the sensory axon terminals in the epithelium and travels to the neuronal cell body via retrograde transport (Figure 7). In animal models, HSV undergoes an initial acute replication within neurons (Leib et al., 1989). Concurrent with, and following clearance of replicating virus, HSV establishes latent infection, in which no replicating virus can be detected (Figure 7). During latent infection, the only viral gene products expressed to high levels are a family of noncoding RNAs known as the latency-associated transcripts (LATs; Figure 8; Stevens

Figure 8 Latently infected neuron expressing the latency-associated transcript (LAT) in its nucleus (red). Mice were infected with HSV-1 via corneal method and sacrificed at 30 days postinfection. The trigeminal ganglia were sectioned and hybridized with a DNA probe that detects LAT (red). Neurons were counterstained for neurofilaments (green). Copyright, Lynne Chang and David Knipe.

Herpes Simplex Virus

et al., 1987). The LATs include a primary, approximately 8 kb transcript that is spliced to give rise to a stable 2 kb intron, which can also be further spliced into smaller introns (Farrell et al., 1991; Spivack et al., 1991; Wagner et al., 1988). Also encoded within the same region of the genomes are six microRNAs (miRNAs; Cui et al., 2006; Umbach et al., 2008; Jurak et al., 2010); small (approximately 22 nts), noncoding RNAs, which bind to target mRNAs and either inhibit their translation and/or promote their degradation. In animal models, the LATs both promote the establishment of latent infection and efficient reactivation (Leib et al., 1989; Thompson and Sawtell, 1997; Bloom et al., 1994b). Roles for the LATs in downregulating lytic cycle gene expression during both the establishment and maintenance of latency have been described (Chen et al., 1997; Garber et al., 1997). Sequences within the LAT region have been found to increase the association of heterochromatin with lytic promoters during latent infection (Wang et al., 2005; Cliffe et al., 2009). miRNAs within the LAT region may also downregulate lytic gene expression at the protein level; miRNAs in the LAT region can downregulate the lytic proteins ICP0, ICP4, and ICP34.5 in transient transfection assays (Umbach et al., 2008; Tang et al., 2008). Expression of the LATs also increases the survival of neurons (Perng et al., 2000; Thompson and Sawtell, 2001), although the mechanism by which the LATs do this is contentious (Thompson and Sawtell, 2000). In particular, whether LATs directly inhibit apoptosis in infected neurons or whether the LATs indirectly inhibit neuronal death as a consequence of downregulation of the lytic cycle genes is not known. Regions of the LAT have been found to inhibit apoptosis in nonneuronal cells (Perng et al., 2000; Henderson et al., 2002; Inman et al., 2001; Ahmed et al., 2002). Studies using LAT mutant viruses expressing proteins that restrict apoptosis have indicated that inhibition of apoptosis in the absence of the LAT increases reactivation (Jin et al., 2005, 2007, 2008). However, in the absence of studies on the effects of expression of antiapoptotic proteins on reactivation of wild-type viruses, it is difficult to conclude that the mechanism by which the LATs promote reactivation is by inhibiting apoptosis. The reasons why infection of neurons, and not other cell types, results in latent infection are not fully understood, although contributing factors have been identified. A cellular component of the transactivator complex, HCF-1 is localized to the cytoplasm in neurons (Kristie et al., 1999). In addition, infection on the terminal axon is more likely to result in latent infection, and this has been linked to slower axonal trafficking of VP16 compared to viral capsids (Hafezi et al., 2012). Therefore, neither VP16 nor HCF-1 is available to transactivate a gene expression. Expression of the LATs initiates from a neuronal specific promoter (Batchelor and O’Hare, 1990; Zwaagstra et al., 1990) and in the absence of LAT expression, a greater proportion of neurons express lytic transcripts during the acute stage of infection (Garber et al., 1997). In combination, all these factors would result in immediate silencing of lytic gene expression and expression of the LATs upon infection of neurons. However, a proportion of latently infected neurons also show evidence of prior lytic gene expression, suggesting that in a subset of neurons, lytic gene expression can first be activated and later switched off to allow the establishment of latent infection (Proenca et al., 2008).

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There is a clear role for the host immune response in clearance of acute lytic infection; disruption of components of the innate and adaptive immune response result in increased lytic replication in animal models (Leib et al., 1999; Lima et al., 2010; Halford et al., 1997; Chee et al., 2003; Peng et al., 2007; Menachery et al., 2010; Knickelbein et al., 2008). However, the role of the immune response in promoting and maintaining latency is less clear. It has been reported that lytic gene expression can still be switched off in the absence of functional B and T lymphocytes (Gesser et al., 1994), indicating that a functional immune response is not essential for the establishment of latent infection. There are also reports that viral specific CD8þ T cells and/or IFN g can block viral gene expression and replication reducing reactivation in explanted ganglia (Decman et al., 2005; Liu et al., 2001, 2000), although whether activated T cells are maintained in proximity to latently infected neurons is contentious (Liu et al., 2000; Held et al., 2011). In humans, immunosuppression is correlated with increased HSV associated disease, although it is possible that the immune system functions to limit lytic replication following a reactivation stimulus and not to prevent reactivation directly.

Reactivation Periodically, the virus reactivates from the latent state (Figure 7). In humans, triggers for reactivation include injury to the tissues innervated by latently infected neurons, or by systemic stimuli including changes in hormone levels, stress, and exposure to UV light (Roizman et al., 2013; Blyth et al., 1976; Sawtell, 1998; Bloom et al., 1994a). At the cellular level, depletion of trophic factors, in particular nerve growth factor (NGF), results in HSV reactivation (Wilcox and Johnson, 1988). NGF-signaling through the TrkA receptor maintains phosphatidylinositol 3-kinase activation (reviewed in Chao, 2003), which in turn maintains mammalian target of rapamycin (mTOR) activity. Inhibition of both these pathways also results in HSV reactivation (Camarena et al., 2010; Kim et al., 2012; Kobayashi et al., 2012). Upon initiation of lytic gene expression, there is evidence that the initial burst of gene expression does not follow the same cascade of gene expression seen during lytic infection (Thompson et al., 2009; Du et al., 2011; Kim et al., 2012). A role for chromatin control in control of HSV gene expression during latency and reactivation is highlighted by the observation that histone deacetylase inhibition can stimulate reactivation from latent infection (Danaher et al., 2005; Neumann et al., 2007). Furthermore, during reactivation, lytic promoters become more associated with euchromatin (Neumann et al., 2007), and removal of the certain repressive modifications are required for reactivation from latency (Liang et al., 2009). Following certain reactivation stimuli, HCF-1 translocates to the nucleus (Kristie et al., 1999) and presumably recruits the histone demethylases and methyltransferases that promote euchromatin association with lytic gene promoters (Whitlow and Kristie, 2009; Narayanan et al., 2007; Liang et al., 2009). However, the intervening steps between a reactivation stimuli and recruitment of proteins that activate lytic gene expression have not been characterized. Ultimately, viral proteins are expressed, limited viral DNA replication occurs and viral proteins and capsids travel in an

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anterograde fashion to the axon terminal, where mature virions are released (Figure 7).

Epidemiology Like other members of the herpesvirus family, the most striking feature of HSV epidemiology is the extraordinarily high prevalence of infection. A large majority (60–90%) of human adults harbor latent herpes simplex viruses (Chayavichitsilp et al., 2009), making them almost a tissue-specific episome of the human genome, or a ubiquitous component of the normal human ‘viral flora’. The epidemiological patterns of HSV infection can be understood on the basis of their underlying biology. Enveloped viruses that most efficiently infect mucosal surfaces (and not intact, keratinized skin) make them pathogens of close contact. Long-term latency with intermittent low level viral shedding mean most transmissions are from asymptomatic carriers to people with whom there is prolonged close contact. The patterns of acquisition and spread vary considerably, however, between HSV-1 and HSV-2. For HSV-1, the epidemiological pattern of spread closely tracks the genealogy of the people infected, because the highest rates of transmission happen between mothers (and siblings) and their infants and children, demonstrated by the high seroprevalence of HSV-1 antibodies among young children (Xu et al., 2006). In contrast, HSV-2 epidemiology closely tracks what is seen for other sexually transmitted pathogens, with incidence of primary infection (and seroconversion) very low during childhood, rising sharply with the onset of sexual activity, and then falling with advancing age. Because seropositivity is lifelong, seroprevalence rises with age even as rates of seroconversion decline. A recent WHO estimate found that in 2003, over half a billion people worldwide were seropositive (and thus latently infected), with over 20 million new primary infections occurring that year (Looker et al., 2008). The strongest epidemiological predictors of HSV-2 seropositivity are lifetime number of sexual partners and the number of partners the partners themselves had (Centers for Disease Control and Prevention, 2010). Of note, the majority of HSV-2 seropositive people do not recall having had symptomatic illness (Langenberg et al., 1999), so the major epidemiological mode of HSV-2 transmission is silent spread among asymptomatic people. In a prospective study of serodiscordant heterosexual couples, 9.7% seroconverted over 334 days, 70% occurring when the source partner was asymptomatic (Mertz et al., 1992). Interestingly, for women, the risk of HSV-2 acquisition was markedly higher if they lacked preexisting HSV-1 antibodies (32 vs 9%). In addition to their primary patterns of spread, HSV-1 and HSV-2 both show marked variations in prevalence over time (Xu et al., 2006), by geographic region (Looker et al., 2008; Smith and Robinson, 2002), by race (Schillinger et al., 2008), and by socioeconomic status. In general, seroprevalence of both viruses has fallen recently in the developed world (Xu et al., 2006) (for HSV-2 reversing an earlier rise during the 1960s through 1980s) and among people of higher socioeconomic status (Zajacova et al., 2009). For example, between 2005 and 2008 the overall seroprevalence of HSV-2 among US

women was 20.9% (Centers for Disease Control and Prevention, 2010), compared to 53.3% in South African women (Johnson et al., 2005). Seroprevalence rates also vary by gender, with rates in females consistently higher than in males (Centers for Disease Control and Prevention, 2010). The distribution of HSV-1 and HSV-2 has also been shifting recently in some groups, with a majority of genital infections in young Caucasian women now found to be HSV-1 (Bernstein et al., 2013).

Clinical Manifestations The principal clinical pattern of HSV infection is a localized primary infection (sometimes asymptomatic) followed by lifelong latent infection of neural ganglia with variable numbers of recrudescences over time. In addition, there are low rates of invasive infection, infection of nonintact skin barriers, and fulminant infection of immunocompromized hosts. Although the risk per person of each of these is low, the very high prevalence of HSV in the population results in a substantial disease burden overall.

HSV-1 Although most infections are asymptomatic, primary HSV-1 infection is also a common, self-limiting cause of febrile illness among infants and young children, typically with the abrupt onset of fever, malaise, and painful orolabial lesions that begin as clusters of erythematous papules progressing over days to vesicles, which then crust over and heal, leaving no scarring (Bader et al., 1978). Adults who do not acquire infection earlier can experience a similar, sometimes severe syndrome when they have a new close contact, including genital HSV-1 lesions in the setting of orogenital exposure (Roberts et al., 2003). Although the infection is self-limiting, patients with more severe cases can have modest decreases in severity and duration of symptoms if treated with an HSV DNA polymerase inhibitor, the nucleoside analog acyclovir (or related compounds) within the first 72 h of clinical illness (Amir et al., 1997). After primary infection, HSV-1 establishes latency in the trigeminal ganglia, with a significant minority of people silently shedding virus at any given time (Kameyama et al., 2006; Knaup et al., 2000; Tateishi et al., 1994). Reactivation occurs at highly variable rates between individuals, with increased rates seen under conditions of physiological stress or UV light exposure (Bader et al., 1978). Reactivation disease is usually much milder than primary infection, with small numbers of vesicles (‘cold sores’) appearing at or near the vermillion border of the lip, and little or no systemic symptoms. People experiencing severe or frequent recurrences may also benefit from acyclovir therapy (Gilbert, 2007; Cernik et al., 2008). HSV-1 infection can also cause invasive disease at a wide variety of anatomical sites either during primary infection or reactivation, the most important of which is HSV-1 encephalitis. This infection, globally the most common cause of fatal sporadic encephalitis, presents with the rapid onset of fever and mental status changes. It is suggested by the presence of lymphocytes and red blood cells in the spinal fluid, and by temporal lobe involvement symptoms and brain imaging

Herpes Simplex Virus findings. It is confirmed by PCR detection of HSV viral DNA in spinal fluid (DeBiasi et al., 2002; Boivin, 2004). Rapid institution of acyclovir therapy can be life-saving but serious neurological sequelae are common. HSV-1 can produce a number of other diseases when virions are able to circumvent the protective barrier of keratinized skin. Introduced onto the conjunctiva, it can cause severe ocular infections such as keratitis, one of the most common blinding infections (Kaye and Choudhary, 2006; Kaye et al., 2000). Contact with cuts on the skin, most often on the fingers, can cause the painful local lesions of herpetic whitlow (Wu and Schwartz, 2007), with abraded skin on athletic mats, herpes gladiatorum (Anderson, 2003), and with eczema skin lesions, the severe, even life-threatening eczema herpeticum (Olson et al., 2008). Finally, HSV-1 can cause serious localized or disseminated disease in immunocompromized hosts, particularly in human immunodeficiency virus (HIV) infection and in bone marrow transplant patients (Meyers et al., 1980). An important feature of these infections is that, in contrast to immunocompetent patients, development of acyclovir resistance is common (Meyers et al., 1980).

HSV-2 HSV-2 shares with HSV-1 the pattern of primary infection (when symptomatic) with painful vesicular-to-pustular lesions (with or without fever) followed by latent infection of neural ganglia and sporadic recrudescences. For HSV-2, however, the lesions are most often genital and the sites of latency are primarily sacral ganglia (Lafferty et al., 1987). A majority of people with symptomatic primary infection will have recurrent infection within a year, with declining frequency after that. The recurrences are usually much less severe – even asymptomatic – and lack fever or systemic signs (Corey et al., 1983; Benedetti et al., 1994), though a small fraction of people, more often women, will have much more frequent recurrences. As with HSV-1, this group of people may benefit from suppressive acyclovir (Mattison et al., 1988). Either during primary or recurrent infection, HSV-2 can cause central nervous system disease, although in contrast to HSV-1, it causes meningitis rather than encephalitis (Kupila et al., 2006). Most of what was formerly designated recurrent aseptic meningitis (Mollaret’s) is now known from PCR studies to represent HSV-2 infection (Schlesinger et al., 1995). HSV-2 infection of the neonate is an uncommon but devastating complication of maternal HSV-2 infection, most often seen where mothers have been recently infected and have active genital shedding of virus (Brown et al., 2003). Neonatal HSV-2 infection can cause meningitis, sepsis, and fulminant disseminated infection, with a mortality of untreated infection exceeding 80% (Whitley et al., 1991). Prompt initiation of high-dose acyclovir at the first suspicion of neonatal HSV-2 infection can substantially decrease mortality (Kimberlin et al., 2001). Finally, as seen with HSV-1, immunosuppression can lead to more severe and treatment-refractory HSV-2 disease. Increased recurrence rates for both these viruses have been seen as an early feature of HIV-1 disease, often before the appearance of more classical AIDS-associated infections. In addition, HSV-2 infection is associated with a two- to fourfold increased

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risk of HIV infection, making HSV a major factor in the spread of HIV worldwide (Corey et al., 2004).

Appendix A: Supplementary data Supplementary video related to this article can be found online at http://dx.doi.org/doi:10.1016/B978-0-12-801238-3.00080-5.

See also: History of Virology; Receptors in Antiviral Immunity; Toll-Like Receptor Function and Signaling; Type I Interferons in Immunity; Viral Pathogenesis; Viruses and MicroRNAs.

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Further Reading Roizman, B., Knipe, D.M., Whitley, R.J., 2013. Herpes simplex viruses. In: Knipe, D.M., Howley, P.M. (Eds.), Fields Virology, 6th ed. Lippincott Williams & Wilkins, Philadelphia, pp. 1823–1897.