The rare HIV-1 gp41 mutations 43T and 50V elevate enfuvirtide resistance levels of common enfuvirtide resistance mutations that did not impact susceptibility to sifuvirtide.
Mutations that are selected at low frequency and/or reside outside the enfuvirtide target region, amino acid 36-45 of gp41, might still be important determinants for drug resistance. This study aimed to investigate the phenotypic impact against enfuvirtide and sifuvirtide of uncharacterized gp41 mutations 42G, 43T and 50V, selected in patients failing enfuvirtide-containing regimens. As single mutations, neither 42G, 43T nor 50V conferred resistance to enfuvirtide. However, 50V increased slightly resistance levels for 36D, 38M, 43D or 43T as did 43T for 38M. All mutants displayed a reduced replication capacity, except 42S, 50V and 36D+/-50V. None of the mutants displayed resistance to the next-generation fusion inhibitor sifuvirtide. This study highlights the necessity to confirm the in vitro effect of infrequently selected mutations as 42G was not associated with enfuvirtide resistance whereas 43T and 50V should be considered as secondary enfuvirtide resistance mutations.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Kris
K
Covens
Sarah
S
Megens
Nathalie
N
Dekeersmaeker
Kabamba
K
Kabeya
Jan
J
Balzarini
Stéphane
S
De Wit
Anne-Mieke
AM
Vandamme
Kristel
K
Van Laethem
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D014779:Virus Replication
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide; C505768:sifuvirtide