Impact of HIV-1 protease mutations A71V/T and T74S on M89I/V-mediated protease inhibitor resistance in subtype G isolates.
OBJECTIVE
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.


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.
Gonzalez
Luis M F
LM
Departamento de Genética, Universidade Federal do Rio de Janeiro, CCS-Bloco A, sala A2-120, Cidade Universitária-Ilha do Fundão, Rio de Janeiro RJ 21949-970, Brazil.
Santos
André F
AF
Abecasis
Ana B
AB
Van Laethem
Kristel
K
Soares
Esmeralda A
EA
Deforche
Koen
K
Tanuri
Amilcar
A
Camacho
Ricardo
R
Vandamme
Anne-Mieke
AM
Soares
Marcelo A
MA
D019943:Amino Acid Substitution / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D017422:Sequence Analysis, DNA
D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1