Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates.
BACKGROUND
Enfuvirtide (ENF) is the first of a novel class of drugs that block HIV gp41-mediated viral fusion to host cells. Viruses with mutations at positions 36-38 in HIV-1 gp41 and/or reduced susceptibility to ENF have been selected both in vitro and in vivo.


METHODS
An analysis of baseline and on-treatment ENF susceptibility in virus samples from Phase II clinical trial patients treated with ENF as functional monotherapy for 28 days (TRI-003) or in combination with oral antiretrovirals for >/= 48 weeks (T20-205, T20-206 and T20-208). Population sequencing identified amino acid (aa) substitutions at positions 36-45 of gp41 in plasma HIV-1. ENF susceptibility of virus isolates was tested in the cMAGI assay and viral DNA was sequenced for selected isolates.


RESULTS
HIV-1 gp41 aa 36-45 were highly conserved in virus from ENF-naive patients, except for a 15% incidence of N42S which did not reduce sensitivity to ENF. Virus from patients experiencing viral load rebound exhibited reduced susceptibility to ENF and substitutions in gp41 aa 36-45. The most common substitutions observed on treatment were at positions 36, 38, 40, 42 and 43. On-treatment changes in the phenotypic susceptibility of virus isolates to ENF were generally associated with genotypic changes in aa 36-45. There was a relatively lower incidence of ENF resistance in patients with baseline sensitivity to more oral antiretrovirals in comparison to patients sensitive to fewer antiretrovirals.


CONCLUSIONS
These data identify the importance of HIV-1 gp41 aa 36-45 in the emergence of resistance to ENF.
Sista
Prakash R
PR
Trimeris Inc. Durham, North Carolina, Roche Biosciences, Palo Alto, California, USA.
Melby
Tom
T
Davison
Donna
D
Jin
Lei
L
Mosier
Sarah
S
Mink
Mike
M
Nelson
Emily L
EL
DeMasi
Ralph
R
Cammack
Nick
N
Salgo
Miklos P
MP
Matthews
Tom J
TJ
Greenberg
Michael L
ML
D000328:Adult; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000627:therapeutic use*; D010641:Phenotype
D004279:DNA, Viral; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide