OBJECTIVES: Non-B human immunodeficiency virus (HIV)-1 subtypes possess several amino acid signatures in the viral protease that distinguish them from subtype B, some of which are reported as secondary drug-related mutations. We have previously shown a strong statistical interdependency of residues 71, 89 and 90 in subtype G, but the impact of substitutions on protease inhibitor (PI) resistance is unknown. PATIENTS AND METHODS: We selected subtype G viruses from patients with diverse amino acid combinations at codons 71 (A/T), 74 (T/S), 89 (I/L/M/V) and 90 (L/M). Viral protease genes were inserted into an HIV molecular clone (HXB2). PI drug susceptibilities of chimeric viruses were determined. RESULTS: In isolates displaying 89I/V in combination with A71 or T74, a reversal to subtype G wild-type 89M was observed after growth in the absence of PI. The presence of 71T in one isolate and 74S in another allowed the persistence of 89I. Mutation 90M conferred intermediate but significant degrees of drug resistance to ritonavir and nelfinavir in subtype G viruses. The combination of 71T or 74S, 89I and 90M resulted in higher levels of resistance to those PIs. CONCLUSIONS: Our results point to the hypothesis that 71T or 74S stabilizes 89I in the protease of subtype G, whose association was previously seen by Bayesian network analyses. The association of 89I with 90M may further increase the PI resistance of subtype G viruses when compared with 90M alone, highlighting novel mutational profiles for drug resistance in this non-B subtype.
OBJECTIVES: Non-B human immunodeficiency virus (HIV)-1 subtypes possess several amino acid signatures in the viral protease that distinguish them from subtype B, some of which are reported as secondary drug-related mutations. We have previously shown a strong statistical interdependency of residues 71, 89 and 90 in subtype G, but the impact of substitutions on protease inhibitor (PI) resistance is unknown. PATIENTS AND METHODS: We selected subtype G viruses from patients with diverse amino acid combinations at codons 71 (A/T), 74 (T/S), 89 (I/L/M/V) and 90 (L/M). Viral protease genes were inserted into an HIV molecular clone (HXB2). PI drug susceptibilities of chimeric viruses were determined. RESULTS: In isolates displaying 89I/V in combination with A71 or T74, a reversal to subtype G wild-type 89M was observed after growth in the absence of PI. The presence of 71T in one isolate and 74S in another allowed the persistence of 89I. Mutation 90M conferred intermediate but significant degrees of drug resistance to ritonavir and nelfinavir in subtype G viruses. The combination of 71T or 74S, 89I and 90M resulted in higher levels of resistance to those PIs. CONCLUSIONS: Our results point to the hypothesis that 71T or 74S stabilizes 89I in the protease of subtype G, whose association was previously seen by Bayesian network analyses. The association of 89I with 90M may further increase the PI resistance of subtype G viruses when compared with 90M alone, highlighting novel mutational profiles for drug resistance in this non-B subtype.
Authors: Gonzalo Yebra; Miguel de Mulder; Leticia Martín; Carmen Rodríguez; Pablo Labarga; Isabel Viciana; Juan Berenguer; María Remedios Alemán; Juan Antonio Pineda; Federico García; Africa Holguín Journal: J Clin Microbiol Date: 2011-12-07 Impact factor: 5.948
Authors: Arthur H Robbins; Roxana M Coman; Edith Bracho-Sanchez; Marty A Fernandez; C Taylor Gilliland; Mi Li; Mavis Agbandje-McKenna; Alexander Wlodawer; Ben M Dunn; Robert McKenna Journal: Acta Crystallogr D Biol Crystallogr Date: 2010-02-12
Authors: Mina Henes; Klajdi Kosovrasti; Gordon J Lockbaum; Florian Leidner; Gily S Nachum; Ellen A Nalivaika; Daniel N A Bolon; Nese Kurt Yilmaz; Celia A Schiffer; Troy W Whitfield Journal: Biochemistry Date: 2019-08-19 Impact factor: 3.162
Authors: Esmeralda A Soares; André F Santos; Luis M Gonzalez; Matthew S Lalonde; Denis M Tebit; Amilcar Tanuri; Eric J Arts; Marcelo A Soares Journal: J Antimicrob Chemother Date: 2009-08-26 Impact factor: 5.790