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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 10Alphaherpesvirus DNA replication

and .

Witebsky Center for Microbial Pathogenesis and Immunology, SUNY at Buffalo School of Medicine, NY, USA

DNA replication in alphaherpesviruses has been the subject of study in bursts over the years. Interest in the subject depends not just on simple curiosity about this central feature of the viral growth cycle, but also because DNA replication is a potentially useful target for antiviral therapy, as has already been shown with agents such as acyclovir. The viral contributions to the mechanism of genome replication are quite well understood but we still are unable to duplicate the in vivo situation in an in vitro assay. Much of the recent interesting work involves the host cell’s contribution to the process, and this seems likely to remain a focus for the future.

Structure of the genome

There are over 30 alphaherpesviruses that infect a wide range of host species. Their genomes fall into two general categories, either herpes simplex (HSV) – like or varicella zoster (VZV) – like, with four or two, respectively, isomeric forms (Fig. 10.1). There is a wide range of G + C content (32%–75%), with a bias towards higher (>50%) numbers. There is also size heterogeneity (125–180 kbp) which, although quantitatively less than the nucleotide composition variation, may be much more significant for the lifestyle of the virus. All alphaherpesvirus genomes contain four general structural components: unique long and short (UL, US) sequences that encode single-copy genes and inverted repeat regions that bound the unique regions; these may contain diploid genes and sequences required for cleavage and packaging of viral DNA (Fig. 10.1). DNA replication initiates at origin sequences (ori), and there are two or three of these in each genome, depending on the virus. Evidence suggests that only one ori is required for viral DNA replication, however, and the importance of multiple origins, if any, remains to be discovered (Roizman and Knipe, 2001; Balliet et al., 2005). Only a few of the alphaherpesviruses have been studied at the molecular level regarding DNA replication (e.g., HSV, VZV, equine herpesvirus type 1 (EHV-1), pseudorabies virus (SuHV-1), and infectious bovine rhinotracheitis virus (BoHV-1). Most of the work, however, has been carried out with HSV, reviewed by Boehmer and Lehman (1997) and Lehman and Boehmer, (1999); the majority of the information presented here will be that gathered for HSV .

Fig. 10.1. The structure of alphaherpesvirus genomes.

Fig. 10.1

The structure of alphaherpesvirus genomes. The upper diagram shows the sequence organization of the herpes simplex virus genome, with the origins of DNA replication shown as oriL or oriS. The lower diagram shows the general layout of the regions of the (more...)

The origins of DNA replication

For those viruses with an oriL, this is found in the middle of the UL segment, in the region lying between DNA polymerase and the major DNA -binding protein for HSV, but not necessarily for other viruses (Telford et al., 1992). The oriS sequences sit in the repeat regions bounding the US region. The two origins in HSV are very similar but not identical (Fig. 10.2), and other alphaherpesvirus origins also have the same general structural features (Telford et al., 1992; Kuperschmidt et al., 1991), to the extent that HSV infection can support limited replication of a VZV ori-containing plasmid (Stow and Davison, 1986), for example. These herpesvirus origins are not dissimilar to other origins in other mammalian viruses, with a dyad symmetry element adjacent to an AT -rich sequence, flanked by binding sites for the origin recognition protein and possibly other factors (Fig. 10.2), implying similar general mechanisms for initiation of genome replication.

Fig. 10.2. The structure of alphaherpesvirus origins of replication.

Fig. 10.2

The structure of alphaherpesvirus origins of replication. Shown above is the HSV -1 oriS sequence. Box Ⅲ is a low-affinity UL 9 recognition site, Box Ⅰ is a high affinity UL 9 binding site and Box Ⅱ has a ten-fold lower affinity (more...)

Location of DNA synthesis

Viral DNA replication takes place in the nucleus. Prereplicative sites form as DNA -protein complexes that appear as punctuate elements by immunofluorescence microscopy, in association with nuclear domain 10 (ND10) (Ishov and Maul, 1996). As synthesis proceeds, larger areas of the nucleus become involved, and are visualized as globular replication compartments (Quinlan et al., 1984). Recently, it has been demonstrated that active viral transcription assists in the association of viral DNA with ND 10 (Sourvinos and Everett, 2002), implying that assembly of transcription and/or replication complexes promote this association. The authors suggest that a critical step in initiating DNA synthesis is ND 10 association, and this idea is supported by work with Epstein–Barr virus, in which postreactivation, but not latent, genomes are ND 10-associated (Bell et al., 2000).

Proteins involved in DNA synthesis

It is generally accepted that, prior to replication, the linear viral DNA initially circularizes; then synthesis initiates at an origin(s) and proceeds bidirectionally to form theta structures. Soon after, synthesis switches to a rolling circle mode, in which genome-sized pieces are cleaved and packaged as they are produced. This all takes place in the presence of UL 9, the origin-binding protein; UL 29 (ICP8), a single-strand DNA -binding protein; UL 30 and UL 42, the DNA polymerase and DNA polymerase processivity factor, which make up the DNA polymerase complex; and UL 5, 52 and 8 which make up the DNA helicase/primase complex. These constitute, at present, the essential alphaherpesvirus replication proteins. The assembly of the viral replication complex appears to be an ordered process, in which UL 9, ICP 8 and the helicase-primase heterotrimer first form replication foci, and the polymerase holoenzyme (UL30 and UL 42) are then recruited; this recruitment process seems to require primer synthesis (Carrington-Lawrence and Weller, 2003). Despite our knowledge of the viral polypeptides required for origin-dependent DNA synthesis in vivo, it has still not been possible to reconstitute this theta mode of replication in vitro. Instead, work has focused on rolling circle replication, which can be demonstrated using a replisome containing oriS and the two viral protein complexes – DNA polymerase/UL42 and the heterotrimeric helicase-primase; the viral SSB (UL29) is not required (Falkenberg et al., 2000).

The origin-binding protein dimerizes and binds to the CGTTCGCACTT ori sequence; it also has ATP -binding and helicase functions. Opening the viral ori appears to involve several viral and cellular proteins; on a superhelical template in the presence of ATP, UL 9 and ICP 8 allowed about half of the oris to unwind, and following addition of the cellular topoisomerase Ⅰ, the extent of unwinding was augmented to >1 kb.

ICP8, the UL 29 gene product, is a classical single-stranded DNA binding protein (SSB), with helix-destabilizing activity. It has been shown to interact with all the other replication proteins (above) and seems likely to be the principal scaffold for the generation of prereplication complexes adjacent to ND 10 sites. Recent work shows that a C-terminal alpha helix is important in binding viral and/or cellular factors, allowing targeting of ICP 8 to specific nuclear sites (Taylor and Knipe, 2003). In addition, it seems to operate in concert with the alkaline endo-exonuclease activity of the virus to constitute a viral recombinase activity similar to that of the bacteriophage lambda (Reuven et al., 2003). In that context, it has recently been shown to stimulate, and regulate, the processivity of, the pseudorabies virus DNase (Hsiang, 2002).

DNA polymerase is a heterodimer, with the UL 30 gene product as the typical polymerase/3′–5′ exonuclease (proofreading) activities, and UL 42 as the processivity factor. The holoenzyme has a broad substrate specificity that allows it to be a useful target for antiviral therapy, as discussed elsewhere in this volume. The UL 42 protein stimulates polymerase activity and increases the fidelity of replication (Chaudhuri et al., 2003); it has been hypothesized to function by interdigitation of its termini, using a hinge region at aa241–261 (Thornton et al., 2000). C-terminal residues in the polymerase polypeptide are important for UL 42 interaction and interference with this may be a useful antiviral tool (Bridges et al., 2000). UL 42 is an unusual processivity factor, in that it binds directly to DNA, unlike the “sliding clamps” such as PCNA and the E. coli β protein. Nevertheless, it seems to resemble PCNA both in its interaction with polymerase (Zuccola et al., 2000) and its ability to slide downstream with polymerase during replication (Randell and Coen, 2001).

The UL 5 and UL 52 polypeptides constitute the core of the helicase–primase complex, with DNA helicase, primase and ATP ase activities. UL 5 and UL 52 also demonstrate DNA -binding activity when they form complexes, and this DNA -binding activity is preferentially to forked substrates, as opposed to single-stranded or duplex molecules (Biswas and Weller, 2001). The contribution of UL 8 to the complex is to work with ICP 8 to promote unwinding activity and to catalyze nuclear localization of the complex. An HSV -1/HSV-2 recombinant, in which UL 5 is the only HSV -2 gene, is non-neurovirulent and defective in DNA replication in neurons. The primary defect was in primase activity, suggesting that interactions between subunits in the complex are vital in ensuring its full catalytic activity (Barrera et al., 1998). Inhibitors of helicase–primase activity have recently been investigated as potential antiviral agents. The most powerful compounds inhibited primase, helicase and ATP ase activities and, as expected, were active against viral mutants resistant to nucleoside-based therapies (Crute et al., 2002).

A second set of proteins with links to DNA synthesis are considered non-essential for replication in cultured cells, but several appear to be essential for “normal” behavior of virus in animal models. These include: pyrimidine deoxynucleoside kinase; alkaline endo-exonuclease; ribonucleotide reductase; uracil N-glycosylase and deoyuridine triphosphatase.

The pyrimidine deoxynucleoside kinase, popularly known as thymidine kinase (TK) phosphorylates a wide range of nucleoside substrates, as well as TMP, and is responsible for the rise in the TTP pool that is characteristic of HSV -infected cells. The enzyme, because of its broad specificity, also acts on the acyclovir family of antivirals, and has been used extensively in gene therapy in combination with ganciclovir and acyclovir (Hayashi et al., 2002). This broad specificity has recently been analysed and seems to depend on the electric dipole moment of ligands interacting with a negatively charged residue at aa 225 (Glu)(Sulpizi et al., 2001). TK -deletion mutants will establish latency in mouse ganglia but do not reactivate, presumably owing to a lack of an equivalent cellular activity. However, viral strains that only produce small quantities of enzyme are able to reactivate with wild-type efficiency (Griffiths et al., 2003).

The UL 12 ORF encodes an endo-exonuclease that is most active between pH 9 and 10; the significance of this is uncertain. This protein interacts with ICP 8 and plays a role in the maturation and packaging of viral DNA; this is consistent with the behavior of UL 12 null mutants, which make DNA and late proteins, but do not produce infectious virus particles efficiently. The hypothesis is that the enzyme acts on gaps and/or nicks in progeny DNA, either to process or repair it on its way towards encapsidation. The UL 12 phosphoprotein and ICP 8 can also work in concert to promote strand exchange, similar to recombination events in lambda phage (Reuven et al., 2003).

Ribonucleotide reductase allows formation of deoxynucleoside diphosphates from ribonucleoside substrates and is not negatively regulated by the high TTP pools in HSV -infected cells, as would be the cellular equivalent. It is made up from the products of two ORFs (UL39, R1 and UL 40, R2) to form a symmetric heterotetramer, and seems to be necessary for viral growth in “resting” cells. There are reports of protein kinase activity associated with the R1 polypeptide of HSV -2, but there is also evidence that, while HSV -2 R1 is itself a substrate for protein kinase activity, the polypeptide does not itself possess intrinsic protein kinase activity (Langelier et al., 1998). Recently it has been shown that an accessory function of the reductase may be to protect HSV -1 infected cells against cytokine-induced apoptosis.

Uracil N-glycosylase (encoded in UL 2) is a repair enzyme that cleaves mutated U residues from the DNA sugar backbone resulting from a cytosine deamination event, subsequent to repair by viral and cellular enzymes. It is curious that the virus should encode an enzyme that is ubiquitous in host cells, but activities may be low in non-dividing cells that the virus encounters in vivo. This may also be the explanation for reduction in neurovirulence and a poor ability to reactivate from latency that is characteristic of UL 2-deletion mutants.

Deoxyuridine triphosphatase (dUTPase), the product of the UL 50 gene, breaks down dUTP, preventing dU incorporation into viral DNA. At the same time, the product of its action, dUMP, is a substrate for the pathway that leads to TTP synthesis. UL 50 null mutants are impaired in their ability to replicate in the central nervous system in mice, although they seem capable of normal growth in peripheral tissues. They also fail to reactivate effectively.

In addition to the viral proteins described above, there are cellular proteins that contribute both essential and/or accessory roles in viral DNA replication. Among the obvious examples of the former are DNA ligase and topoisomerase activities, as well as repair endonuclease activity and an endonuclease G, that may contribute to maturation of the viral genome (Huang et al., 2002). Among the latter are the numerous cellular enzymes that contribute substrates for DNA synthesis, and that are found in all dividing cells. There will likely be additional cellular proteins found, however, such as the promyelocytic leukemia protein (PML) that is recruited to replication foci following the arrival of the polymerase complex (Carrington-Lawrence et al., 2003), and the OF -1 protein that has a function in initiation of replication (Baker et al., 2000). It also contains the Ku70/Ku80 heterodimer which is present in origin-specific DNA -binding complexes in primates and yeast (Murata et al., 2004).

DNA replication and the cell cycle

HSV downregulates host cell DNA synthesis during lytic infection, implying that the normal cell cycle is dysregulated by the virus. The reason for this, presumably, is to allow the virus maximum access to DNA precursors, replication sites and replication proteins that would otherwise be involved in cellular genome synthesis. In a parallel scenario, it has been shown that, using the inhibitor roscovitine, cyclin-dependent kinases are required for HSV DNA replication, even although the early viral proteins required for synthesis are all present (Schang et al., 2000). Cell cycle arrest has been shown to involve the viral ICP 0 protein, using mechanisms that appear to be both p53-dependent and p53-independent. One mechanism whereby ICP 0 is effective, is through arresting the cycle at the G1->S stage, blocking cells at the pseudo-prometaphase stage of mitosis (Lomonte and Everett, 1999). The data suggest that viral factors other than ICP 0 may be involved in this cell cycle block but that ICP 0 alone may be responsible for the mitotic block. The authors make the point that ICP 0 expression is incompatible with the growth of a cell population. One additional viral protein that affects the cell cycle is ICP 27; it blocks the cycle at S phase, through inhibiting the phosphorylation of pRb (Song et al., 2001). Thus, the virus has evolved a number of different mechanisms to interfere with normal cell cycle progression, emphasizing the potential importance of this step in the viral growth cycle.

Maturation and packaging of viral DNA

The a sequences of the HSV genome (Fig. 10.1) constitute the cis-acting signals for cleavage of the newly synthesized DNA, resulting from rolling circle replication, into genome-sized pieces for packaging into capsids. The DR 1 repeat sequences that flank the a sequences contain the actual cleavage site, and two unique regions, Uc and Ub, are next to the genomic ends. A fragment, Uc/DR1/Ub, is sufficient to constitute a minimal packaging signal, and elements inside the U sequences can be found in other herpesvirus genomes; these are the pac elements. Data suggest that these pac sequences contain signals for both initiation and termination of packaging (White et al., 2003). The proteins involved in the process are UL 6, UL 15 and UL 28 in HSV -1, and these are sufficient for cleavage of the concatameric DNA, as well as their packaging into procapsids. UL 6 likely constitutes the gateway on the preformed capsid for entry of the genome and is present at one vertex, while a UL 15/UL28 complex has the properties of the engine that drives the genome into the procapsid. UL 6 is capable of specific interaction with both UL 15 and UL 28 (Hodge and Stow, 2001). A fourth protein, UL 25, seems to play a final role in the packaging process, prior to the movement of nucleocapsids into the cytoplasm.


Homologous recombination is a frequent event in herpesvirus infected cells, and it has been used experimentally to investigate gene functions, for example, by generation of HSV -1/HSV-2 intertypic recombinants. Viral DNA molecules that are undergoing replication are the best substrates for recombination and the genomic inversions that give rise to the different isoforms of the HSV genome are generated through recombination involving the repeat regions. While it seems likely that cellular enzymes or other proteins will be important in the process, there are clearly roles for viral gene products. For example, ICP 8, as outlined earlier, appears potentially to be a key player in the recombination process. In in vitro assays, it promotes strand exchange in conjunction with the viral helicase-primase and catalyzes single-strand invasion in an ATP -independent manner (Nimonkar and Boehmer, 2003). It also may be involved in single-strand transfer, in collaboration with the HSV endo-exonuclease activity, UL 12. The 5′–3′ exonuclease activity of this protein shares homology with the lambda exonuclease (Redalpha) that is known to be essential for homologous recombination in the phage. It is proposed that the two viral proteins work in concert to promote strand exchange, shown experimentally by generating a gapped circle and a displaced strand from an M13 duplex DNA molecule and an M13 single-stranded circular DNA molecule. Interestingly, UL 12 polypeptide that lacked nuclease activity was incapable of catalyzing this experimental recombination (Reuven et al., 2003). In addition to the various roles that recombination might play in the virus life cycle, it has been proposed that recombination may also be important for the switch that occurs between the early theta mode of replication of viral DNA and the mainstream rolling circle mode, in a way reminiscent of the mechanisms occurring in the lytic phase of lambda replication (Boehmer and Lehman, 1997).


Alphaherpesvirus latency, as typified by HSV, is characterized by a lack of infectious virus in latently infected neural tissue and expression of specific LATs (latency-associated transcripts). VZV, on the other hand, has no LAT s, and expresses a restricted set of transcripts and proteins seen in the early phases of normal lytic infection. Calculations of the numbers of viral genomes present in latently-infected neurons have shown a small but significant number to be present; in HSV, a recent estimate gives a mean of 178 per LAT -positive neuron using laser capture microdissection (Chen et al., 2002). This number is not dramatically different from less sophisticated measurements on VZV -infected ganglia. This raises the issue of how this number of genomes arises, and the simplest explanation is that initial infection of the neuron proceeds by the normal lytic route, initiates some DNA replication (only through a theta-like mode?) but is quickly curtailed by factors within the cell. At present, we have no clues as to what constitutes this inhibitory mechanism. Reactivation must involve renewed viral DNA synthesis and, indeed, the presence of several viral proteins of the “non-essential-in-cell-culture” variety is necessary to allow the process to proceed. In addition, there is a proposal that the cellular C1 factor, responsible for assembly of transcriptional enhancer complexes, is normally missing from neuronal nuclei but present soon after reactivation (Kristie et al., 1999). Thus, as with other herpesvirus systems (e.g., EBV), it is likely that the HSV reactivation is initiated through production of gene regulatory viral proteins.

Future directions

Future investigation is likely increasingly to focus on the host cell’s contribution to viral genome replication. The recent interest in nuclear structures will provide the field with a new set of findings that may provide the clues necessary to allow faithful replication of the in vivo situation in an in vitro environment. Aside from replication, the host cell also plays a role in the repair/recombination events that characterize the viral growth cycle, and these contributions also remain to be precisely defined. Finally, the issue of latent vs. lytic viral behavior has focused primarily on transcription and its control; perhaps it is now time to look more closely at viral DNA replication in latently infected cells.


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