Antiviral Therapies: RNA Viruses

The results show that genome modifications involve both base mutations and processivity impairments. Viral quasi-species, in particular RNA viruses, have RNA-dependent polymerases with mutation rates(2) in the range of 104 to 106 times that of their hosts polymerases. In addition, most viral polymerases have a poor processivity(3).

Both modifications are linked to the absence of proof-reading activity of RNA virus polymerases, and the absence in the latter of a sliding clamp, a ring-like structure speeding up dramatically the rate of catalysis of cellular polymerases and preventing their diffusion from the nucleic acid template.

In an attempt to evade the host’s immune defenses, viral quasi-species manage to set their mutation rates and processivities close to the limit of infectivity, even if thereby a large proportion of the viral progeny lose infectivity. For instance, the RNA-dependent polymerase of HIV1 (a reverse-transcriptase) has in vivo a fidelity of 1 to 3 10-5 mutations/bp/cycle, a poor processivity and a high rate of recombination.

Infection of a TCD4+ or a macrophage cell by a single HIV1 releases in less than a day a progeny of several hundred new viruses, most of which underwent mutations and therefore are undetected by the circulating immune defenses. Among them, only ~10% are infectious, whilst the remaining are decoys for the immune system and contribute to TCD4+ proliferation, delivering thereby abundant new HIV1 targets.

Thanks to a deep understanding of those mechanisms, Vigilent has opened a new line of therapy, inspired by Iolas strategy and covered by granted patents USPTO 6,727,059; INPI (France ) 9905905; EPO 1200097 split into INPI (France) 1200097 and DPA (Germany) P0048398.3.