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Background   HIV type-1 (HIV-1) resistance to enfuvirtide (ENF) is mediated by mutations in the HR1 domain of gp41. We have previously shown that some of these mutations are selected in the context of env backgrounds that are not dominant before exposure to ENF, suggesting that particular env environments could facilitate phenotypic expression of HR1-mediated ENF resistance.Methods   Envelope clones, representing the viral quasispecies present in the longitudinal follow-up of a patient who failed ENF-based salvage therapy, were tested for ENF susceptibility and Env-related replicative capacity. ENF resistance mutations in HR1 were introduced or back-mutated in representative clones to evaluate their phenotypic effect in different genetic contexts.Results   The ENF resistance levels produced by the introduction of mutation V38A in pretherapeutic env sequences were significantly lower than those of env clones harvested after viral escape, and in which V38A was naturally selected. Back-mutation of V38A from these clones resulted in a strong loss in ENF resistance, but these clones retained significant residual resistance, again strongly suggesting the role of determinants outside of HR1 in HIV-1 resistance to ENF. By contrast with changes in resistance, addition or removal of HR1 mutations in env clones had little effect on viral replicative capacity.Conclusions   The development of ENF resistance in vivo is a concerted coevolutionary process whereby HR1 mutations are selected within env variants that permit their optimal phenotypic expression.

In vivo selection by enfuvirtide of HIV type-1 env quasispecies with optimal potential for phenotypic expression of HR1 mutations