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Cellular Factors Influencing Semliki Forest Virus Vector Biology

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Cellular Factors Influencing Semliki Forest Virus Vector Biology Gene Therapy (2005) 12, S111–S117 & 2005 Nature Publishing Group All rights reserved 0969-7128/05 $30.00 www.nature.com/gt CONFERENCE PAPER Cellular factors influencing Semliki Forest Virus vector biology E Piver1, C Collin2, A Diatta1, P Vaudin1 and J-C Page`s1 1Universite´ Franc¸ois Rabelais, The Vector Group, Faculte´ de Me´decine, Tours, France; and 2Biochemistry, Trousseau University Hospital, Tours, France Viral vectors are currently the best tools for gene delivery in transduction, and transgene expression, in view of the cellular a therapeutic setting, especially for in vivo use. Alphaviruses, factors that affect each individual step. Classical virology will a family of positive singlestranded RNA viruses, have been benefit from the knowledge accumulated studying vectors, and engineered to allow the formation of a highly efficient replicon. such work will shed light on crosstalk between intruding Using these replicons, it is possible to generate recombinant viruses and their hosts. Ultimately, these data should help the particles. Parental viruses and recombinant vectors share design of vectors adapted to specific target cells. certain pathways while interacting with their target cells. In this Gene Therapy (2005) 12, S111–S117. doi:10.1038/ review, we describe the consecutive events leading to sj.gt.3302625 Keywords: VLP; endocytosis; TLR; IFN and SFV vectors Introduction noteworthy that vectors would take advantage of a precise and complete knowledge of the alphavirus cell cycle. Virally driven tumour cytotoxicity is an expanding field A companion paper by Lundstrom10 gives a useful in antitumoral research.1–6 Technically, it relies on two overview of the main steps of the alphavirus life cycle, exclusive modus operandi, tumour-restricted cytolytic introducing the essential features needed to understand replicative viruses or suicidal recombinant viral vectors. alphavirus vectors. In addition, we will comment on Whereas several viral genera have been employed for the use of an unconventional trans-complementation both approaches, only adenovirus based agents are approach for the production of SFV vectors.16 We have currently in the clinic.7,8 recently described an efficient procedure for the mobi- Among the viral vectors, those derived from alpha- lization of SFV replicons by the means of virus-like viruses occupy a specialized niche.9,10 Semliki Forest particles (VLP) (Figure 1). These particles are made of a Virus (SFV) and Sindbis Virus (SV) are the main two membrane-anchored vesicular stomatitis virus glyco- alphaviruses from which vectors have been obtained.11,12 protein (VSV-G) protein forming a lipo-protein shell In agreement with their biology, these vectors are encapsulating a full-length SFV replicon.16 More recently predominantly adapted to high levels of transient we have shown that the biological behaviour of the VLP transgene expression. This results from an optimized resembles that of viral particles in several ways, leading cytoplasmic genomic replication combined with the to cell entry (Diatta et al unpublished data). We also cytotoxic effect induced by a number of virally encoded observed unexpected features that triggered a series proteins.9 The clinical applications of SFV-derived of experiments dedicated to the understanding of the vectors are therefore restrained to situations where such relationship established between the SFV replicon and its a pattern of expression appears suitable, namely, genetic- cellular environment. based vaccination and the eradication of an invasive cell As noticed in other viral taxa, such as retroviruses, proliferation, as observed in cancer. Moreover, recent viruses and cells have evolved several molecular mechan- experimental reports showed that alphavirus-derived isms that rule their biological association.17 In the present vectors harbour an unexpected specificity to replication review, we will concentrate on alphavirus-derived vectors in tumour cells.13–15 Nevertheless, numerous features of biology with a specific interest on cellular factors. Host SFV biology remain open to clarification. This knowledge gene products exert a dual effect; on the one hand, some might lead to technological improvements and extend proteins positively participate in viral replication and, the use of SFV-derived vectors. conversely, when induced upon infection, other cellular In order to develop better tools, two topics are the focus products aim to hamper viral propagation. of ongoing studies, biosafety issues as well as the understanding of cancer cell replication specificities. It is Replicon is the basic structure of SFV vectors Correspondence: J-C Page`s, Universite´ Franc¸ois Rabelais, EA 3856-IFR 136, The Vector Group, Faculte´ de Me´decine 10 Bd Tonnelle´, 37000 Tours, Shortly after the genetic organization and sequence of France alphavirus was determined, several vector systems were Cellular factors and SFV vectors E Piver et al S112 Figure 1 Representation of the different steps in VLP production process. At day 1, the transcomplementing, envelope expressing plasmid is transfected; followed, at day 2, by a DNA form of the replicon. Viral harvest is performed at day 3. CMV: immediate-early cytomegalovirus promoter. VSV-G: vesicular stomatitis virus glycoprotein. NsP: nonstructural proteins. R.S: retroviral sequence. IRES: internal ribosome entry site. EGFP: enhanced GFP. engineered to promote gene delivery and expression vectors must preserve some features of the regular viral from various strains of alphavirus, including SFV.18,19 cycle while eliminating others. The most striking The most striking feature of an SFV-derived vector is its difference between nonreplicating viral vectors and the genetic structure, which allows the generation of a self- wild type parental virus, resides in the late events replicating element, the replicon. A SFV replicon is governing particle formation, which are nondesirable composed of a single RNA that contains all the genetic most of the time and are therefore hampered in the case information needed for self-amplification and transgene of vectors. Conversely, early events that allow efficient expression. There are two ways by which the replicon transgene delivery must be indistinguishable in the two could be delivered to a target cell.4,20–22 The most species. It is noteworthy that each step of the viral cycle common system is based on RNA or DNA transfection. is susceptible to target-cell-specific modulation. For in vivo use, the formation of recombinant particles is possible through trans-complementation. However, in Entry the case of recombinant particle formation, safety issues Classically, the sequential events leading to delivery of must be considered since recombination events are the viral genomic material are divided into entry, frequent and lead to fully replicative autonomous 23 including decapsidation, which is followed by the particles. Genetic modification of the trans-comple- cytoplasmic addressing of the viral genome.27 At the mentation vectors has recently improved the safety of 23 end of the latter process, the viral genome is addressed to SFV vectors. Considering the biosafety, the VLP offer the cellular compartment where it will ultimately a relevant alternative to recombinant SFV. One key replicate and drive expression of the viral gene products. advantage conferred by the VLP comes from the Efficient, virally promoted, cellular entry is the raison heterologous origin of the trans-complementing materi- 16 d’eˆtre for the use of recombinant viruses in gene transfer. al. Of note, in this approach, replicon packaging is not All viruses, including alphaviruses, enter a target cell based on an interaction between the SFV capsid and using a defined pathway that involves a virally encoded a sequence contained within the nonstructural protein protein expressed at the particle surface and a cellular (nsP) 2 open reading frame of the full length SFV RNA. receptor at the plasma membrane.27 First, we shall Thus, we had to find a substitutive method to achieve the consider the envelope protein density at the particle exclusive packaging of a complete replicon. Indeed, Rolls 24,25 surface, together with the receptor exposed at the cell et al showed that alike VLP were able to package surface. For retroviruses, these two features are known genomic RNA as efficiently as sub-genomic. The sub- to directly influence entry.28–30 In the case of SFV vectors, genomic RNAs that don’t have auto-replicative capabil- the high amount of envelope proteins generated through ities are not suitable for gene transfer approaches. sub genomic translation appears to prevent a deficient Therefore, we have introduced several mutations into envelope filling of the particles. Conversely, receptor the internal 26S promoter. In the absence of sub-genomic based restriction has been described for SFV.31 While the RNA synthesis, we obtained an exclusive packaging of precise receptor for SFV is still unknown, it is acknowl- the fully autonomous genomic RNA. To obtain success- edged to be widely expressed.32 Therefore, cells resistant ful transgene expression, it was hence necessary to use to transduction might express the protein but fail to an internal translation initiation, which can efficiently be make it available. In some circumstances, this defect in obtained by using a picorna virus internal ribosome 26 receptor accessibility could be circumvented by the use entry sequence (IRES). of nonspecific chemical agents that promote enveloped virus–cellular membrane interaction.31
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