Do RNA viruses require genome cyclisation for replication?

• We suggest that the functional requirement for base pairing between the 5′ and 3′ ends of the dengue virus RNA genome does not necessarily require cyclisation.
• All available literature data are consistent either with single genome cyclisation in cis, or with multiple genome dimerisation or concatomerisation in trans.
• The concatomer form is likely favoured under normal cellular conditions.
• The concatomer form can potentially contribute to other essential viral functions besides replication.

Complementary sequences at the 5′ and 3′ ends of the dengue virus RNA genome are essential for viral replication, and are believed to cyclise the genome through long-range base pairing in cis. Although consistent with evidence in the literature, this view neglects possible biologically active multimeric forms that are equally consistent with the data. Here, we propose alternative multimeric structures, and suggest that multigenome noncovalent concatemers are more likely to exist under cellular conditions than single cyclised monomers. Concatemers provide a plausible mechanism for the dengue virus to overcome the single-stranded (+)-sense RNA virus dilemma, and can potentially assist genome transport from the virus-induced vesicles into the cytosol.