Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA

Vere Hodge, R Anthony

I have mentioned above that Pharmasset understood that all the drugs with the highest genetic barriers were nucleoside/tide analogues -why should that be so? Hugh Field 8 and I devised the term 'back door escape route'. We illustrated the concept using the HIV protease. When treating an HIV patient with a single PI, the first (primary) resistance mutation will decrease the inhibition by the antiviral drug but perhaps by a small degree. Then other mutations (secondary) will further decrease the inhibition by the drug. These mutations are usually near the active centre of the protease. Further mutations (tertiary) may be remote from the active centre and may not decrease the inhibition of the drug but restore some of the lost functionality of the protease. By carful combination of PIs with different resistance mutations, it may be that none of the spontaneously arising mutant proteases can be both resistant to the drugs and be a competent enzyme -the 'front door is locked'. However, there is a 'back door escape route' -the viral RNA encoding both the protease and that for the cleavage sites (the protease substrate) can co-mutate so that both the enzymic activity and the substrate change. The altered protease is no longer inhibited by the PIs, it has 'escaped through the back door'. The 'back door escape route' is not available to the viral polymerases because the natural nucleotides are absolutely required for building the viral DNA/RNA. Hence, careful combinations of nucleoside/tide analogues have given the drug therapies with the highest genetic barriers.