Assay of HIV gp41 amino acid sequence to identify baseline variation and mutation development in patients with virologic failure on enfuvirtide.
In this study, we retrospectively assessed a gp41 genotypic assay in 404 enfuvirtide-naïve individuals (340 clade B, 64 non-B clade) to determine the prevalence of baseline polymorphisms and in 41 patients virologically failing enfuvirtide to determine correlates of resistance to this agent. Conserved and polymorphic regions of gp41 were identified in clade B isolates, with 127 of 328 codons (38.7%) being highly conserved (<1.0% variation) and 74 of 328 codons (22.6%) being partially conserved (1.0-5.0% variation). Polymorphisms were observed throughout gp41 in non-B clade virus sequences compared to the clade B reference strain, ranging from 53 natural substitutions in clade D to 76 in clade A. Insertions were common at positions 3, 105, 215 and 276. In the patients failing enfuvirtide, mutations were detected in the 10 amino acid region at positions 36-45 in all plasma virus sequences. Six additional mutations were selected outside of the common region which may be clinically significant at positions 33, 73, 75, 126, and 138. Two or three mutations at positions 36-45 were observed in the majority of plasma virus sequences from patients with virologic failure following the use of enfuvirtide. Further study is required to determine the clinical relevance of the clade related polymorphisms and the new mutations identified in the patients with virologic failure.
Loutfy
M R
MR
University of Toronto, Toronto, Ont., Canada. mloutfy@nygh.on.ca
Raboud
J M
JM
Montaner
J S G
JS
Antoniou
T
T
Wynhoven
B
B
Smaill
F
F
Rouleau
D
D
Gill
J
J
Schlech
W
W
Brumme
Z L
ZL
Mo
T
T
Gough
K
K
Rachlis
A
A
Harrigan
P R
PR
Walmsley
S L
SL
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020029:Base Pairing; D001483:Base Sequence; D002170:Canada / Q000453:epidemiology; D003062:Codon; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D005260:Female; D014644:Genetic Variation; D015700:HIV Envelope Protein gp41 / Q000097:blood / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000097:blood / Q000627:therapeutic use*; D015658:HIV Infections / Q000097:blood / Q000453:epidemiology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D010446:Peptide Fragments / Q000097:blood / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D015995:Prevalence; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D015203:Reproducibility of Results; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
D003062:Codon; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; D000077560:Enfuvirtide