Increased polymorphism in the HR-1 gp41 env gene encoding the enfuvirtide (T-20) target in HIV-1 variants harboring multiple antiretroviral drug resistance mutations in the pol gene.
BACKGROUND
Sequence variations in HR-1 gp41 env gene region encoding the target for T-20 have previously been reported among patients naive to inhibitory fusion.


OBJECTIVE
To evaluate whether a previous therapeutic history of patients could have an impact on a differential evolution of the gp41 polymorphism.


METHODS
We assessed the genetic polymorphism within the critical HR-1 gp41 env gene region in HIV-1 variants from 108 T-20-naive patients (Groups I-III) and 12 patients receiving T-20 as part of a salvage regimen (Group IV). T-20-naive patients included 50 patients exhibiting variants harboring resistance mutations to NRTIs, NNRTIs, and PIs (Group I), 24 patients with variants harboring resistance mutations for NRTIs and/or NNRTIs (Group II), and 34 antiretroviral drug-naive patients (Group III).


RESULTS
In T-20-naive patients whose HIV harbored resistance mutations to NRTIs, NNRTIs, and/or PIs, the mean number of synonymous mutations (ds) per patient was decreased and the mean number of nonsynonymous (da) mutations per patient was increased, resulting in a significant decrease in the mean Sigmads/Sigmada ratio as compared with antiretroviral drug-naive patients (Group III; 4.1 vs. 11.6; P < 0.0001). The mean number of polymorphic mutations in HR-1 gp41 per patient was two-fold higher in patients exhibiting antiretroviral drug resistance mutations (Groups I and II) than in antiretroviral drug-naive patients (Group III; 0.41 vs. 0.20; P < 0.05).


CONCLUSIONS
Our observations indicate that the HR-1 gp41 T-20 target is subjected to high genetic variability, including intrinsic polymorphism and selection of T-20 resistance mutations under T-20 intake, that is increased by the presence of resistance mutations to NRTIs, NNRTIs, and/or PIs. Our data provide a basis for a potential impact of previous antiretroviral drug history on the therapeutic efficacy of T-20.
Si-Mohamed
Ali
A
Laboratoire de Virologie, Hôpital Européen Georges Pompidou, Paris, France. ali.simohamed@egp.aphp.fr
Piketty
Christophe
C
Tisserand
Pascaline
P
LeGoff
Jérôme
J
Weiss
Laurence
L
Charpentier
Charlotte
C
Kazatchkine
Michel D
MD
Bélec
Laurent
L
D018432:Drug Resistance, Multiple / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D015751:Genes, pol / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*
D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide