title: Relative replicative fitness of human immunodeficiency virus type 1 mutants resistant to enfuvirtide (T-20).
abstract: Resistance to enfuvirtide (ENF; T-20), a fusion inhibitor of human immunodeficiency virus type 1 (HIV-1), is conferred by mutations in the first heptad repeat of the gp41 ectodomain. The replicative fitness of recombinant viruses carrying ENF resistance mutations was studied in growth competition assays. ENF resistance mutations, selected in vitro or in vivo, were introduced into the env gene of HIV-1(NL4-3) by site-directed mutagenesis and expressed in HIV-1 recombinants carrying sequence tags in nef. The doubling time of ENF-resistant viruses was highly correlated with decreasing ENF susceptibility (R(2) = 0.859; P < 0.001). Initial fitness experiments focused on mutants identified by in vitro selection in the presence of ENF (L. T. Rimsky, D. C. Shugars, and T. J. Matthews, J. Virol. 72:986-993, 1998). In the absence of drug, these mutants displayed reduced fitness compared to wild-type virus with a relative order of fitness of wild type > I37T > V38 M > D36S/V38 M; this order was reversed in the presence of ENF. Likewise, recombinant viruses carrying ENF resistance mutations selected in vivo displayed reduced fitness in the absence of ENF with a relative order of wild type > N42T > V38A > N42T/N43K approximately N42T/N43S > V38A/N42D approximately V38A/N42T. Fitness and ENF susceptibility were inversely correlated (r = -0.988; P < 0.001). Similar results were obtained with recombinants expressing molecularly cloned full-length env genes obtained from patient-derived HIV-1 isolates before and after ENF treatment. Further studies are needed to determine whether the reduced fitness of ENF-resistant viruses alters their pathogenicity in vivo.
authors.affiliation: Section of Retroviral Therapeutics, Brigham and Women's Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02139, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Prakash
authors.initials: P
authors.lastname: Sista
authors.forename: Françoise
authors.initials: F
authors.lastname: Giguel
authors.forename: Michael
authors.initials: M
authors.lastname: Greenberg
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D011995:Recombination, Genetic; D014779:Virus Replication
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide