Evolution of genotypic resistance to enfuvirtide in HIV-1 isolates from different group M subtypes.
BACKGROUND
Enfuvirtide is active against isolates from different HIV-1 subtypes. In vitro and in vivo studies reveal that resistance mutations are primarily found within the region spanning amino acid 36-45 of gp41. However, most studies include only subtype B strains, while it is known that especially the env region is very divergent among subtypes.


OBJECTIVE
To analyze the gp41 HR1 genetic evolution during failure of enfuvirtide-containing salvage regimens in 19 HIV-1 patients infected with strains from different group M subtypes.


METHODS
The gp41 sequence was determined at baseline and upon failure in 19 patients. For a subset of 7 patients, samples were available after discontinuation of enfuvirtide.


RESULTS
Our results confirmed the conserved nature of the HR1 region. Escape mutants during chronic treatment with enfuvirtide were mainly observed within region 36-45. One novel mutation was identified, i.e. S42G in a subtype A1 strain.


CONCLUSIONS
Different subtypes escape enfuvirtide selective pressure through similar mutational patterns, however a new S42G variant was observed. The in vivo selection of S42G suggests that it might play a role in enfuvirtide resistance. Therefore, it could be considered as a candidate mutation to be included within drug resistance interpretation systems.
Covens
Kris
K
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. kris.covens@uz.kuleuven.ac.be
Kabeya
Kabamba
K
Schrooten
Yoeri
Y
Dekeersmaeker
Nathalie
N
Van Wijngaerden
Eric
E
Vandamme
Anne-Mieke
AM
De Wit
Stéphane
S
Van Laethem
Kristel
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D019143:Evolution, Molecular; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology*; D016879:Salvage Therapy / Q000379:methods; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide