HIV-1 mutants that are resistant to the fusion inhibitor enfuvirtide (ENF; T-20) have reduced replicative fitness in culture compared to wild-type (WT) virus, researchers report in the May issue of the Journal of Virology.
As lead investigator Dr. Daniel R. Kuritzkes told Reuters Health, "mutations in HIV-1 that make it resistant to ENF come at a cost, and result in a weakened virus that grows more slowly than drug-sensitive strains."
Dr. Kuritzkes of Brigham and Women's Hospital, Boston and colleagues used growth competition assays to study the effects of ENF resistance mutations on replicative viral fitness of recombinant HIV-1 isolates.
HIV-1 isolates carrying HR-1 mutations associated with ENF resistance in vitro and in vivo displayed reduced replication rates compared to WT and were less fit than WT isolates.
Linear regression showed that the doubling time of ENF-resistant viruses was highly correlated with decreasing susceptibility to ENF (p<0.001). Similarly, the researchers note "the relative order of fitness was inversely correlated with the reduction in ENF susceptibility and was reversed in the presence of drug."
Preliminary results in patients have also shown that ENF-resistant viruses are less fit than WT in the absence of the drug.
"The potential clinical significance," Dr. Kuritzkes added, "is that viruses that grow more slowly may not achieve the same high virus load in patients as wild-type, and may contribute to some persistent benefits of therapy even in the setting of drug resistance. This benefit remains to be proven, however."
J Virol 2004;78:4628-4637.