Effect of naturally-occurring gp41 HR1 variations on susceptibility of HIV-1 to fusion inhibitors.
BACKGROUND
Sequence variations in the gp41 heptad repeat 1 (HR1) region have been identified in some treatment-naive HIV-1-infected patients but it remained elusive whether they confer resistance to fusion inhibitors.


OBJECTIVE
To evaluate whether naturally occurring sequence variations in the HIV-1 group M gp41 HR1 region affect the sensitivity to inhibition by T-20 and T-1249.


METHODS
Site-directed mutagenesis was used to generate HIV-1 NL4-3 mutants containing changes in the gp41 HR1 domain which have been previously identified in treatment-naive patients infected with various HIV-1 group M subtypes. HIV-1 variants were produced by transient transfection of 293T cells and used to determine viral infectivity and sensitivity to the fusion inhibitors T-20 and T-1249.


RESULTS
Most naturally occurring sequence variations in the HR1 domain did not reduce viral infectivity. Three of the 10 HIV-1 variants analysed containing a single substitution of L33V, which is frequently present in subtype D isolates, or combined changes of L54M/Q56K or L34M/L54M/Q56R showed about fivefold reduced sensitivity to inhibition by T-20. In comparison, none of these HR1 sequence variations conferred resistance to T-1249.


CONCLUSIONS
Some naturally occurring sequence variations in the gp41 HR1 region reduce sensitivity of HIV-1 to inhibition by T-20 but not T-1249.
Chinnadurai
Raghavan
R
Department of Virology, Universitätsklinikum, Ulm, Germany.
Münch
Jan
J
Kirchhoff
Frank
F
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000494:pharmacology
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C474741:peptide T1249; D000077560:Enfuvirtide