The M184V substitution in human immunodeficiency virus type 1 reverse transcriptase delays the development of resistance to amprenavir and efavirenz in subtype B and C clinical isolates

Abstract

The M184V substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), encoding high-level resistance to lamivudine (3TC), results in decreased HIV-1 replicative capacity, diminished RT processivity, and increased RT fidelity in biochemical assays. We assessed the effect of M184V on the development of resistance to the nonnucleoside RT inhibitors efavirenz (EFV) and nevirapine, and to the protease inhibitor amprenavir (APV) in tissue culture. Genotypic analysis revealed differences in EFV resistance-conferring mutations in subtype B (K103N) versus subtype C (V106 M), and the appearance of both was significantly delayed in the M184V-containing variants compared with the wild type (WT). Similarly, there was a marked delay in the emergence of mutations associated with APV resistance (I54 M/L/V) in subtype B viruses harboring M184V compared with paired WT viral isolates.

FIG. 1.

Selection of resistance to drugs in tissue culture. (A) Stepwise progression of EFV concentrations and development of resistance in a paired experiment involving the WT and M184V-containing 4246 clinical isolates of subtype B origin. (B) Selection of resistance to EFV in WT and M184V-containing clinical isolates of subtype C origin. Concentrations of EFV are expressed as changes in mean IC₅₀ values (n-fold). Arrows indicate time to first appearance of V106 M. Values represent the mean ± standard error of the mean (n = 6 and 2 for WT and M184V isolates, respectively). (C) Selection of resistance to APV in WT and M184V-containing clinical isolates of subtype C origin. Concentrations of APV are expressed as changes in mean IC₅₀ values (n-fold). Arrows indicate time to first appearance of the I54L mutation.

FIG. 1.

Selection of resistance to drugs in tissue culture. (A) Stepwise progression of EFV concentrations and development of resistance in a paired experiment involving the WT and M184V-containing 4246 clinical isolates of subtype B origin. (B) Selection of resistance to EFV in WT and M184V-containing clinical isolates of subtype C origin. Concentrations of EFV are expressed as changes in mean IC₅₀ values (n-fold). Arrows indicate time to first appearance of V106 M. Values represent the mean ± standard error of the mean (n = 6 and 2 for WT and M184V isolates, respectively). (C) Selection of resistance to APV in WT and M184V-containing clinical isolates of subtype C origin. Concentrations of APV are expressed as changes in mean IC₅₀ values (n-fold). Arrows indicate time to first appearance of the I54L mutation.