Combination of V106I and V179D Polymorphic Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confers Resistance to Efavirenz and Nevirapine but Not Etravirine

Abstract

Etravirine (ETV) is a second-generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI)introduced recently for salvage antiretroviral treatment after the emergence of NNRTI-resistant human immunodeficiency virus type 1 (HIV-1). Following its introduction, two naturally occurring mutations in HIV-1 RT, V106I and V179D, were listed as ETV resistance-associated mutations. However, the effect of these mutations on the development of NNRTI resistance has not been analyzed yet. To select highly NNRTIresistant HIV-1 in vitro, monoclonal HIV-1 strains harboring V106I and V179D (HIV-1 V106I and HIV-1 V179D ) were propagated in the presence of increasing concentrations of efavirenz (EFV). Interestingly, V179D emerged in one of three selection experiments from HIV-1 V106I and V106I emerged in two of three experiments from HIV-1 V179D . Analysis of recombinant HIV-1 clones showed that the combination of V106I and V179D conferred significant resistance to EFV and nevirapine (NVP) but not to ETV. Structural analysis indicated that ETV can overcome the repulsive interactions caused by the combination of V106I and V179D through fine-tuning of its binding module to RT facilitated by its plastic structure, whereas EFV and NVP cannot because of their rigid structures. Analysis of clinical isolates showed comparable drug susceptibilities, and the same combination of mutations was found in some database patients who experienced virologic NNRTI-based treatment failure. The combination of V106I and V179D is a newly identified NNRTI resistance pattern of mutations. The combination of polymorphic and minor resistance-associated mutations should be interpreted carefully.

In Vitro HIV-1 Evolution in Response to Triple Reverse Transcriptase Inhibitors & In Silico Phenotypic Analysis

“…Although previous reports suggest that the V106I mutation alone does not confer resistance to NVP in vitro [50], [51], we estimated a low-to-moderate resistance by this mutation, which may be explained by the genetic background of isolates #2/3.…”

Nonnucleoside Reverse Transcriptase Inhibitor-Resistant HIV Is Stimulated by Efavirenz during Early Stages of Infection

“…However, ETR did not demonstrate stimulation. Etravirine (ETR) is unlike EFV and nevirapine (NVP) in that it has a elastic structure that allows more flexibility in binding to the NNRTI binding pocket (17,28,31). We show here that the ETR IC 50 of K101EϩG190S is low, indicating that the flexibility of ETR allows it to bind to the NNRTI binding pocket despite the presence of the K101E and G190S mutations.…”

In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

“…Part of the reason why the L100I mutant is not seen in the clinical setting may be the high trough concentration of EFV (ϳ5 M) in plasma at 24 h after dosing, which is more than enough to suppress an L100I mutant, thereby requiring an additional mutation that gives a L100I/K103N double mutant to overcome the selective pressure. In addition, although the V179D mutant is not listed as the prevalent NNRTI-associated virus, it has often emerged with other mutants under the selective pressure of EFV (30). Moreover, in the resistance selection with RPV, the E138K substitution represented the first substitution in the two out of three mutation pathways, which is consistent with the finding that the E138K mutant was the most frequently selected mutant in a clinical setting, although it was often associated with M184I/V (9, 10).…”