General Replication Strategies for RNA Viruses

Introduction
The replication of viral RNA genomes is unique considering that the host cell does not contain a RNA dependent RNA polymerase. To overcome this constraint, the majority of RNA viruses encode their own RNA polymerase that is either packaged with the virus genome or is synthesised shortly after infection.

Single strand RNA viruses can be classified into three classical groups according to the polarity of their genomes, which in turn dictates the strategy for viral replication (White and Fenner, 1994). The first group, viruses with (+) sense RNA genomes include the Picornaviridae, Flaviviridae, Togaviridae, Caliciviridae and the Coronaviridae. The linear RNA genomes of the Picornaviridae and Flaviviridae are polycistronic and act as mRNA that is translated into a viral polyprotein which is subsequently cleaved into individual viral polypeptides, one of which is a RNA dependent RNA polymerase. This polymerase uses the (+) sense input RNA as a template for the transcription of (-) sense RNA which in turn can act as a template for the production of nascent (+) sense RNA. This newly transcribed (+) sense RNA has 3 possible functions;

(i) mRNA

(ii) a template for production of additional (-) strands or

(iii) packaged as progeny virus.

In contrast to the above replication strategies the Togaviridae and the Coronaviridae use a slightly different mechanism in which subgenomic mRNA species are used for the transcription of the structural proteins. Only the 5' two thirds of the Togaviridae (+) sense genome is translated that results in the synthesis of a polyprotein that is post- translationally cleaved into the non-structural proteins one of which is a RNA dependent RNA polymerase. This polymerase then synthesises full length (-) sense RNA from which two species of (+) sense RNA are copied;

(i) virion RNA that can be packaged or can act as a template for more (-) strand synthesis

(ii) a smaller subgenomic mRNA species that is translated into a polyprotein from which the structural proteins are derived.

The Coronaviridae replicate using a similar mechanism in which a subgenomic 3' nested set of overlapping (+) sense mRNA molecules are synthesised for the translation of the structural proteins. All the (+) sense RNA viruses share a common theme in that their genomes all have the ability to act as a mRNA thereby eliminating the need for the virus to package a RNA polymerase.

The second group, comprising the Orthomyxoviruses, Paramyxoviruses, Bunyaviruses, Arenaviruses and Rhabdoviruses all have (-) sense RNA genomes. The genomes of these viruses must serve two functions, firstly to serve as a template for transcription to generate (+) sense RNA and secondly as a template for replication. Upon entry into the host cell the (-) sense genome is transcribed to generate (+) sense monocistronic RNA that serves as mRNA for the production of viral proteins which initiate genome replication. This (+) sense RNA also serves as a template for the synthesis of (-) strand genomic RNA's. In contrast to the (+) sense RNA viruses described above, (-) strand viruses must package a functional RNA polymerase to initiate transcription of their (-) sense genome.

The Retroviridae make up the third group in which the RNA genome does not function as a (+) or (-) sense molecule but acts as a template for the production of viral DNA. This is achieved by RNA dependent DNA polymerase (reverse transcriptase) that is packaged with the RNA genome. The resulting viral DNA integrates into the host cell genome to provide the template for viral RNA synthesis by host derived mechanisms.