Uncommon Mutations at Residue Positions Critical for Enfuvirtide (T-20) Resistance in Enfuvirtide-Naive Patients Infected With Subtype B and Non-B HIV-1 Strains

Abstract

Enfuvirtide (T-20) is the lead compound of the new class of antiretroviral drugs called fusion inhibitors. T-20 resistance-associated mutations located in the heptad repeat 1 (HR-1) domain of gp41 have been described in vitro and in clinical trials. In this study, the authors investigated the primary genotypic T-20 resistance in subtype B and non-B HIV-1 strains from patients at the beginning of their follow-up in the Luxembourg HIV Cohort as well as the emergence of primary resistance to T-20 in patients who had long-term infection with subtype B HIV-1 strains. HR-1 fragments including the gp41 amino acid 36-45, T-20-sensitive region were screened for amino acid variation. No classic T-20 resistance-associated mutations were identified in subtype B or non-B isolates. However, several uncommon mutations were found at residues 37, 39, and 42 for subtype B isolates and at residue 42 for a subtype non-B isolate. The results indicate that primary genotypic T-20 resistance seems to be rare in HIV-1, regardless of subtype or prior antiretroviral therapy (excluding fusion inhibitors). However, episodic variation within HR-1 can occur and needs further phenotypic evaluation in accurate fusion inhibitor resistance assays.

Emergence and Evolution of Enfuvirtide Resistance following Long-Term Therapy Involves Heptad Repeat 2 Mutations within gp41

“…The genetic background of individual isolates may determine different genetic routes to resistance. The HR1 domain is highly conserved across group M subtypes (10,25,36,38). By comparison, studies of the genetic diversity of the HR2 domain reveal greater sequence variability (7,10).…”

Impairment by Mucosal Adjuvants and Cross-Reactivity with Variant Peptides of the Mucosal Immunity Induced by Injection of the Fusion Peptide PADRE-ELDKWA

“…In contrast with the gp41 mutations induced by the synthetic peptide enfuvirtide (T-20), which render the virus resistant to this treatment (15,29), the variations in the ELDKWA sequence may not impair the protection by sIgA Abs. Only three variants, corresponding to a change of aa 670 or 671, were described in primary isolates or in strains obtained by immune selection (26,32).…”

Human Immunodeficiency Virus (HIV) gp41 Escape Mutants: Cross-Resistance to Peptide Inhibitors of HIV Fusion and Altered Receptor Activation of gp120

“…In vitro selection studies with T20 (31) or an overlapping C peptide (C34) (1) identified a region in the N-terminal part of the N-HR (residues 33 to 38 in gp41 or residues 544 to 549 in Env, corresponding to the Los Alamos numbering for the reference HXB2 clone) as being important for resistance, with mutations frequently occurring in the highly conserved GIV sequence. Mutations in the same region and extending slightly more C terminal were also generated in patients treated with T20 (32,38) and were found to occur naturally in treatmentnaive subjects whose viruses showed relative resistance to T20 (10,11). In addition, residues in the C-HR have been shown to increase resistance to T20 in the absence of mutations in the N-HR (19,29).…”