Swarm Intelligence in Cell Entry Exclusion Phenomena in Viruses and Plasmids: How to Exploit Intelligent Gene Vector Self-Scattering in Therapeutic Gene Delivery

Abstract

Many naturally occurring viral and bacterial gene transfer systems present ‘superinfection interference’ phenomena, where expression of additional viral genomes or bacterial plasmids in cells previously infected with a homologous virus or plasmid is limited or altogether absent. The lack of expression of superinfecting homologous genetic material could be due to either denial of its cell entry where a failed cell entry attempt is followed by the return of the superinfecting genomes back into the infecting pool, or, alternatively, to a block of transfer, expression or replication of the superinfecting genomes, where these genomes are being deactivated and eventually destroyed. The distinction between these two scenarios is important because the return of the superinfecting genomes back into the pool of circulating infectious genomes allows productive examination of such superinfection interference phenomena within the abstract framework of swarm intelligence, where viral or plasmid genomes are being viewed as individual ‘agents’. Signaling between mobile agents is a crucial element of swarm intelligence. Thus, in superinfection interference, the denial of cell entry to the superinfecting viral/plasmid genomes (‘circulating’ agents) by the cell-resident viral/plasmid genomes (‘settler’ agents) can be regarded as a signaling event. In virology and plasmid biology, occurrences of denial of cell entry to superinfecting genomes can be met in various settings; the most commonly used terms for these phenomena are ‘cell entry exclusion’ and ‘cell surface exclusion’.

So, being concerned with the intelligent swarm-level behavior, this chapter is focused only on the ‘strict non-admittance’ subset of the cell entry exclusion phenomena where the superinfecting agents are recycled back into the ‘circulating’ infectious pool and are not retained and destroyed by the recipient cells. Considered within the framework of swarm intelligence, these genome agents will exhibit intelligent swarm-based self-scattering behavior. In general, such signaling from the ‘settler’ agents to the homologous ‘circulating’ agents can be accomplished through the knockout of a viral/plasmid receptor or another positive gene transfer factor (passive denial of entry) or through the expression of a gene transfer rejection factor (active denial of entry). This chapter illustrates swarm-based intelligent self-scattering behavior with appropriate examples from known superinfection interference phenomena and conjectures how such behavior of viral/plasmid genomes can be exploited for gene vector scattering needs in therapeutic gene delivery with viral and non-viral gene vectors.

It is anticipated that that intelligent self-scattering of gene delivery agents in gene vector swarms can be employed in artificial gene transfer systems delivering therapeutic genes to human cells in order to avoid undesired multicopy gene conveyance and, thus, to achieve uniform transgene copy-number distribution and transgene expression at an unvaried curatively-effective level in target cells. Thus, it is expected that the exploitation of the intelligent self-scattering capability of swarms of therapeutic gene vectors will find a wide range of applications in gene therapy, particularly where, on the one hand, therapeutic gene delivery is required to be highly concentrated and efficient and, on the other hand, uniform transgene dosage is critical for the optimal curative effect.