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The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), major human pathogen whose lifestyle is based on a long-term dual interaction with the infected host characterized by the existence of lytic and latent infections, has allowed the development of potential vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous system, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases and targeted infection of specific tissues or organs. Three different classes of vectors can be derived from HSV-1: replication-competent attenuated vectors, replication-incompetent recombinant vectors and defective helper-dependent vectors known as amplicons. This chapter highlights the current knowledge concerning design, construction and recent applications, as well as the potential and current limitations of the three different classes of HSV-1-based vectors.

Introduction

The human herpesviruses are an important family of viruses, which become established in various tissues for the life of the host.^1,2 Herpes simplex virus (HSV), is a complex human neurotrophic virus that after initial infection and lytic multiplication at the body periphery, generally at oral or genital epithelial cells, enters in sensory nerve endings innervating the site of multiplication and it is retrograde transported to the nucleus of sensory neurons.^3,4

The genome is a linear double stranded DNA of 152 kb encoding at least 80 gene products. The genome is replicating by a rolling circle mechanism forming head-to-tail concatamers. During the replication, the presence of inverted repeats sequences flanking the two unique segments of the genome (unique long UL and unique short US) are causing the formation of four isomers equally infectious (Fig. 1).^3,5

Figure 1

Herpes simplex virus type 1 genome. The rolling circle replication mechanisms, essential and non-essential accessory genes are depicted.

The infectious virus particle comprehends an icosahedral capsid, which contains the viral DNA genome in association with core proteins. Around the capsid there is an amorphous layer known as the tegument, containing some 20 different proteins with structural and regulatory roles, surrounded by an external envelope containing different glycoproteins involved in different functions, among which the first steps of binding and entry into the host cell. Once the de-enveloped particle has entered the cytoplasm, it is transported through association with microtubules to the nuclear membrane where the viral DNA is released into the nucleus through the nuclear pores;⁶ all the viral replication, from the transcription to the assembly of a new capsid, takes place into the nucleus. Following the release of the viral DNA into the nucleus, the viral genome circularizes and a cascade is initiated with the transcription of five immediate early (IE) genes (infected cell protein ICP4, ICP27, ICP0, ICP22, ICP47) through the binding of a viral protein present in the tegument (VP16), in combination with cellular factors, to the enhancer element present in all IE promoters (TAATGARAT).⁷ The products of the above genes are responsible of the transactivation of the early genes (E) which are encoding enzymes and DNA binding proteins required for the viral synthesis; the IE and E are followed by expression of late genes (L) which products are principally structural proteins of the capsid, tegument and envelope (primarily viral structural components).^3,5

Following natural infection the virus is know to be axonal transported from the periphery to the cell body of the sensory ganglion where establishes a lytic or a latent infection.⁸ HSV-1 persists in the latent state in the nervous systems of the host for a lifetime where the viral genome persists in an epichromosomal state associated with histones without integrating into the host genome.⁹ During a latent infection the virus is in a relative quiescent state where the transcription is limited to a single region of the viral genome and only a group of latency-specific RNAs are detectable in the nuclei of neuronal infected cells. Due to several stimuli, the virus can be reactivated from the latency and usually by anterograde transport gets back to the site of primary infection where it starts a new lytic cycle. Only in few cases the viral particle is retrograde transported to the central nervous system (CNS) and starts a latent or a lytic infection, which evolves in encephalitis.^10,11 The newly replicated virus transported anterograde, usually to a site at or near the portal of entry, may cause a localized cold sore disease lasting 2-10 days with subsequent remission when the cold sores disappear. Over time, periods of remission generally increase in length and the duration of cold sores decrease, until the person rarely has active disease. This process is regulated by specific immunity developed by the patient against the virus.¹² The virus infection is, however, life-long and can be retriggered in some individuals by specific events, such as sunburn, stress or other infections.^13,14

HSV-1 Genome and HSV-Derived Vectors

The complete knowledge of the HSV sequences and progress of molecular techniques has leaded to the development of HSV as a vector for several potential applications in human health.^15-19 These include (i) delivery and expression of human genes to the nervous system cells,^20,21 (ii) selective destruction of cancer cells,^22,23 (iii) prophylaxis and immunotherapy against tumors^24,25 and (iv) prophylaxis against infections with HSV and other infectious diseases.^26,27

In the viral genome there are approximately 80 gene products that can be classified as immediate early (IE or α), early (E or β) and late (L or γ) depending on their kinetics of expression during replication. The viral genes can also be categorized according to whether they are essential or non essential for virus replication (Fig. 1). Essential genes are required to produce new infectious viral particles in permissive cell culture infections. Non essential, or accessory, genes encode products that are not absolutely required in cell culture but are important for optimum lytic replication or affect the natural life cycle of the virusin vivo, contributing to host range, pathogenesis, or latency. The viral DNA contains at least 37 essential genes. The US region of the genome contains only one essential gene encoding the glycoprotein D, which offers the opportunity to replace large segments of viral sequences with foreign DNA.^4,28,29 The modified HSV genome should be able to accommodate up to 40-50 kb of exogenous sequences. However, the modification of these viruses to reduce pathogenicity and increase safety often results in the loss of viral activities, which are required for efficient gene delivery and life long association with the host.

In recent years, new technologies have allowed researchers to get deeper into these problems.³⁰ The challenge for many research groups is to develop the tools to render these organisms harmless yet effective for targeted gene transfer and appropriate gene expression. Vectors based on HSV type 1 are currently a) amplicon vectors, b) replication-defective viruses and c) genetically engineered replication-competent viruses with restricted host range.^19,31

Amplicon Vectors

Amplicon vectors are HSV-1 particles identical to wild type HSV-1 from the structural, immunological and host-range points of view, but which carry a concatemeric form of a plasmid DNA, named the amplicon plasmid, instead of the viral genome.^32-34 Amplicon vectors possess several advantages as gene delivery vehicles: a) a large transgene capacity (150 kb); b) the repetitive character of the genome carried by the amplicon particle ensures the introduction of multiple copies of the transgene per infected cell; c) the ability to infect a wide variety of cell types, including dendritic cells; d) the ease of vector construction; e) the limited toxicity due to the lack of viral coding sequences.

Amplicons are bacterial plasmids that contain one or more transgene cassettes and two non coding viral sequences, an origin of DNA replication (ori) and a DNA cleavage/packaging signal (pac) and they require a helper system to be produced. In the presence of HSV-1 helper functions, a circular amplicon can be replicated and amplified as head-to-tail concatemers and packaged into HSV-1 particles as approx 152 kb linear DNA (Fig. 2).³⁵ Classically, amplicon vectors were prepared in cells transfected with the amplicon plasmid and superinfected with helper HSV-1. As the helper virus was generally a replication-defective mutant of HSV-1, the amplicon stocks were produced in transcomplementing cell lines. However, the use of standard HSV-1 as helper resulted in the production of helper-contaminated vector stocks.^36,37 The contaminant helper particles, even if defective, induced significant cytotoxicity and inflammatory responses, preventing their use in gene therapy or vaccination protocols.³⁰ To overcome these obstacles, different helper systems that produce essentially helper-free vector stocks have been recently developed.³⁸ The last generation of helper system consists of the entire HSV-1 genome, without pac signals, cloned as a bacterial artificial chromosome (BAC) inE. coli supplying the full set of transacting HSV-1 functions.^39,40 Another different helper system recently developed is based on the deletion, by Cre/loxP-based site-specific recombination, of the packaging signals of the helper virus in the cells that are producing the amplicons.⁴¹

Figure 2

Structure and mechanism of packaging of the amplicon vector.

Replication-Defective Vectors

The replication-defective viruses are viral vectors where “essential” genes forin vitro viral replication are either mutated or deleted. Therefore, these mutants cannot grow except in transformed cell lines, where they are complemented in trans. To date, several replication-defective vectors have been constructed in which the IE genes, expressing infected cell proteins (ICP) 0, 4, 22, 27 and 47, have been deleted in various combinations. IE genes are expressed shortly after viral entry into the host cell and are required for initiation of a cascade of E and L viral gene transcription. ICP4 and ICP27 are essential for replication and the deletion of one or both of these genes requires adequate complementing cell lines capable of providing in trans the proteins encoded by deleted viral genes.^42-44 ICP0, 4 and 27 are responsible for E and L gene expression.^45,46 Beside its transcriptional functions, ICP27 also affects the splicing, polyadenylation and stability of mRNAs. ICP0 is a promiscuous transactivator acting on ICP6 gene, which encodes the viral ribonucleotide reductase large subunit and possesses a hybrid promoter, which is activated as an IE and an E function.^47,48 ICP22, the viral product that might be involved in sequestering of cellular DNA polymerase⁴⁹ is phosphorylated by two accessory genes UL13 and US3-encoded proteins^50-52 and is required for the optimal expression of the ICP0 protein. Deletion of the ICP22 IE gene can be responsible for an over expression of ICP0.⁵³ ICP47 inhibits MHC class I antigen presentation contributing to the virus escape from the immune surveillance.^54-56 The “first generation” of replication-defective HSV-1 based vectors consisted of mutants deleted in the single essential IE gene encoding ICP4, namely d120.⁴⁵ Although these vectors show reduced pathogenicity and can be used to efficiently transfer and transiently express reporter genes in brain, they are nonetheless cytotoxic for neurons in culture. Cell lines that complement ICP4 and ICP27 have permitted the construction of a “second generation” of highly defective mutants.^43,57-59 To date, several replication-defective vectors have been constructed in which ICP0, ICP4, ICP27, ICP22 and ICP47 genes have been deleted in various combinations.^43,58 Deletion of all five IE genes (ICP 0, 4, 22, 27 and 47) prevents virus toxicity for cells at high multiplicity of infection, allowing the vector gene to persist in cells for long periods^60-62 demonstrating that the residual cytotoxicity of the “first generation” of replication-defective HSV-1 based vectors results from the expression of the other four IE genes.²⁸ The multiply deleted mutants show an unusually prolonged transgene expression from the ICP0 IE promoter or the HCMV IE promoter in neurons.⁶³ The advantages of these second generations of replication-defective vectors are characterized by absence of early and late viral gene expression and provide enough space to introduce distinct and independently regulated expression cassettes for different transgenes.⁴³

Attenuated HSV Vectors

Deletion of some non essential viral genes results in viruses that retain the ability to replicatein vitro, but are compromised in vivo, in a context dependent manner.^64,65 Among the limitations to the use of HSV is the fact that wt virus is highly pathogenic and cerebral injection causes fatal encephalitis. Toxic and/or pathogenic properties of the virus must, therefore, be disabled prior its use as a gene delivery vector.

Several genes involved in HSV replication, virulence and immune evasion, which are non essential for viral life cyclein vitro, have been identified. These genes are usually involved in multiple interactions with cellular proteins, which optimize the ability of the virus to grow within cells. Understanding such interactions has permitted the deletion/modification of these genes, alone or in combination, to create HSV mutants with a reduced ability to replicate in normal quiescent cells, but that can replicate in tumor or dividing cells. These attenuated viruses harbor further modification so they also serve as therapeutic gene delivery vehicles.^65,66

Many HSV-1 and HSV-2 genes that are non essential in culture alter virulence in animal models. Among these genes, the ones encoding thymidine kinase (TK), ribonucleotide reductase (RR), the virion-host shut off (Vhs)⁶⁷ and the ICP34.5 proteins have been extensively studied.⁶⁸TK is involved in optimizing nucleic acid metabolism for virus growth and is necessary for efficient replication in neurons. RR is necessary for the conversion of rNTPs to dNTPs in neurons, which are otherwise lacking but necessary for the synthesis of new viral DNA during virus replication.⁶⁹ The Vhs function of HSV causes rapid destabilization of host RNAs and translational arrest.⁷⁰ Vhs also destabilizes viral messages, resulting in over accumulation of IE and E genes during lytic infection.^70-72 The ICP34.5 neurovirulence factor has been found to be essential for HSV pathogenicity.⁷³ It appears to provide multiple functions to the virus life cycle, one of which is to block the arrest in translation, which usually occurs in virus-infected cells as an antiviral response preventing virus replication. This effect is mediated through the cellular PKR kinase, which phosphorylates the translation initiation factor eIF2α, thereby stopping translation. ICP34.5 recruits protein phosphatase 1a, to rephosphorylate eIF2α, allowing protein translation and continued virus replication. Tumor cells often display an impaired PKR pathway and/or elevated levels of eIF2α, that allow replication of ICP34.5-deleted viruses, as the inactivation of the PKR response is less critical in this contest.^74,75 Secondly, ICP34.5 seems to be involved in allowing new virions to become packaged and leave infected cells in a cell type-specific fashion. Consequently, in non permissive cells in the absence of ICP34.5 the nucleocapsids are retained in the nucleus and a productive infection cannot ensue.

Use of non replicating viruses or non viral systems as vectors can limit the maximum achievable efficiency of gene transfer. In contrast, use of replicating vectors to allow replication of genes delivered initially to a small number of cells and their subsequent transfer to neighboring cells, as infection spreads, can significantly increase the efficacy of gene delivery.^76-78 Attenuated HSV vectors have been tested as live viral vaccines, as oncolytic viruses and as gene therapy vectors to deliver transgenes to the nervous system.

Engineering Techniques

Alterations of the HSV genome can be achieved in a number of ways. These usually require a two-step process (named: marker transfer/marker rescue) in which portions of the herpes genome, which have been cloned into a plasmid vector, are first modifiedin vitro. The plasmid DNA is then cotransfected into cultured cells with infectious viral DNA and recombinant viruses are selected. Several methods have been described to insert DNA sequences into the viral genome. Efficient recombination into specific sites within the viral genome has been achievedin vitro using a recombination system derived from phage P1.⁷⁹ It is also possible to enhance the frequency of recombination.⁵⁹ The initial requirement is the insertion of a reporter gene such as β-galactosidase (lacZ) cassette flanked byPacI orPmeI restriction enzyme sites not otherwise found in the viral genome. The second phase is the substitution of the reporter gene with other foreign cDNAs by digestion of the vector DNA withPacI orPmeI to remove thelacZ gene and subsequent repair of the vector genome by homologous recombination with a transgene expression plasmid. Potential recombinant identified by a “clear plaque” phenotype after X-gal staining arose at high frequency (80-100%) (Fig. 3).⁵⁹ A different procedure involves transfection of cells with overlapping cosmids containing appropriate insertion or deletions. Expression of genes contained in cosmids leads through recombination to the construction of full-length viral genome.^80,81 To select recombinant vectors it is critical to have a system by which to identify successful recombinants. The viralTK gene is particularly useful site for insertion since its inactivation does not affectin vitro the replication of the virus.TK mutants can be easily selected in the presence of bromovinyl deoxyuridine or acyclovir.^82,83 Another marker system involves disruption of non-essential viral envelope glycoprotein genes, such as the ones encoding gC or gE. Recombinant viruses are identified by loss of an antigenic determinant of the glycoprotein using specific monoclonal antibodies (black or white plaques staining).

Figure 3

Mechanism of construction of recombinant viruses by classical homologous recombination (marker transfer/marker rescue) and using the “PacI system”.

Traditionally, recombinant HSV vectors have been generated through homologous recombination between the HSV genome and a recombination plasmid, which usually requires laborious screening or selection and can take several months. Recent advances in bacterial artificial chromosome (BAC) technology have enabled cloning of the whole HSV genome as a BAC plasmid and subsequent manipulation inE. coli. Thus, we sought a method to generate recombinant HSV vectors more easily and quickly using the bacterial recombination machinery.^84,85

BAC cloning requires insertion of mini F plasmid sequences and antibiotic resistance genes into the viral genome and the length of these BAC backbone sequences is usually greater than 6 kb in total. Insertion of BAC sequences into the wild-type HSV genome (152 kb) will increase the genome length to ∼158 kb and there will be no space left for the insertion of additional sequences. To avoid deleterious effects of the BAC sequences, including growth defects and potential transmission between bacteria and man, some herpesvirus BAC clones have been constructed with loxP site-flanked BAC sequences, which can be removed by Cre recombinase.^86-88

HSV-1 Based Vectors Applications

Acknowledgements

This work was supported by MIUR-FIRB-2001 (RBNE0127YS-002), by grants from the Istituto Superiore di Sanità (ISS), the Italian Concerted Action on HIV-AIDS Vaccine Development (ICAV), the Italian Ministry for the University and Scientific Research (FISR), the Italian National Institute of Health (Program Stem Cells, CS 126.1), as well as by the French societies Association Franaise contre les Myopathies (AFM) and Association pour la Recherche sur le Cancer (ARC) and from grants form European Commission (THOVLEN project and HEVAR project, FP6).

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