Drug-resistant viruses may repair impaired fitness by mutations outside the drug target site.

Evaluation of: Ray N, Blackburn LA, Doms RW: HR-2 mutations in human immunodeficiency virus type 1 gp41 restore fusion kinetics delayed by HR-1 mutations that cause clinical resistance to enfuvirtide. J. Virol. 83(7), 2989-2995 (2009). During the treatment of HIV infection with viral fusion inhibitors derived from HIV-1 gp41 heptad repeat (HR)-2 regions, drug-induced mutations have been observed not only in the HR-1 region that contains the target sites for the inhibitors, but also the HR-2 region, which is outside the inhibitor target site. Using a kinetic cell-cell fusion assay, Ray et al. have demonstrated that the HR-1 mutation, which helps viruses to escape from treatment challenge, significantly delays fusion kinetics, leaving viruses more vulnerable to the host immune defense system, thus reducing the fitness of the virus. However, the mutations in the HR-2 region restore the delayed fusion kinetics close to its original level, partially repairing the impaired fitness caused by the mutations in the drug target site. The work sheds new light on the mechanism of HIV-1 drug resistance, which may be used for the development of new HIV fusion inhibitors with improved efficacy and drug resistance profiles.