Enfuvirtide (T-20) resistance-related mutations in HIV type 1 subtypes B, C, and F isolates from Brazilian patients failing HAART.
The synthetic peptide T-20 (enfuvirtide, EFV) represents the first compound approved by the FDA known as entry inhibitors (EIs). The resistance mutations associated with this new class of antiretroviral drug are located in the first heptad repeat (HR1) region of gp41. Amino acid changes in codons G36D/S, I37V, V38A/M/E, Q39H/R, Q40H, N42T, and N43D can confer resistance to EFV. In this work we investigated the presence of resistance mutations that occur in patients never treated with EFV and failing HAART with protease inhibitors (PIs), nucleoside reverse transcriptase (RT) inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). This knowledge can reveal whether this salvage therapy can be effective in patients failing HAART. For this, we amplified 65 samples from plasma isolates and than sequenced a fragment of 416 nt encompassing the HR1 and HR2 regions (amino acids 33-170 of gp41). The subtype distribution among the 65 isolates was 45 (69.23%) subtype B, 9 (13.85%) subtype C, 7 (10.77%) subtype F1, and 4 (6.15%) mosaics B/F1, B/C, F1/C, and C/F1/B. We found a high prevalence (7.6%) of EFV-associated mutation G36D in this cohort of patients failing HAART therapy, five isolates from subtype B (11.11% within this group). In contrast, when 1079 sequences from drug-naive patients were analyzed, only one showed the G36D substitution. This finding indicates a strong association between the selected position G36D and HAART therapy (p < 0.0001). The isolates that possess these mutations can develop resistance to EFV more rapidly. Nevertheless, more information about the impact of these mutations in salvage therapy with EFV in patients failing HAART must still be obtained.
Oliveira
A C A
AC
Laboratory of Molecular Virology, Department of Genetics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Martins
A N
AN
Pires
A F N P C
AF
Arruda
M B
MB
Tanuri
A
A
Pereira
H S
HS
Brindeiro
R M
RM
D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D023241:Antiretroviral Therapy, Highly Active; D001938:Brazil; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / 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; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D055815:Young Adult
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide