Evolution of protease inhibitor resistance in the gag and pol genes of HIV subtype G isolates

• Published in: Journal of antimicrobial chemotherapy Vol. 65; no. 7; pp. 1472 - 1476
• Main Authors: Knops, Elena, Däumer, Martin, Awerkiew, Sabine, Kartashev, Vladimir, Schülter, Eugen, Kutsev, Sergey, Brakier-Gingras, Léa, Kaiser, Rolf, Pfister, Herbert, Verheyen, Jens
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-07-2010; Oxford Publishing Limited (England)
• Subjects: Amino Acid Substitution; Antiretroviral drugs; Correlation analysis; Drug Resistance, Viral; Evolution, Molecular; Gag cleavage site mutations; gag Gene Products, Human Immunodeficiency Virus; Gag non-cleavage site mutations; Genotype; HIV; HIV - drug effects; HIV - genetics; HIV - isolation & purification; HIV Infections - virology; Human immunodeficiency virus; Humans; Medical treatment; Molecular Sequence Data; Mutation; Mutation, Missense; non-B subtypes; pol Gene Products, Human Immunodeficiency Virus - genetics; Polymorphism, Genetic; Protease inhibitors; Protease Inhibitors - pharmacology; Russia; Sequence Analysis, DNA; Russia
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkq129

Objectives To analyse HIV Gag cleavage site (CS) and non-CS mutations in HIV non-B isolates from patients failing antiretroviral therapy. Patients and methods Twenty-one HIV isolates were obtained from patients infected with HIV subtype G during an outbreak in Russia 20 years ago. Most patients were failing antiretroviral therapy when genotyping was performed. Results HIV Gag CS mutations accumulated in protease inhibitor (PI)-resistant HIV isolates and were correlated with the presence of three or more PI resistance mutations. Only 1 of 11 HIV isolates carrying major protease mutations did not harbour treatment-associated CS mutations. Natural polymorphism 453T, often found in HIV non-B subtypes, seems to favour the selection of CS mutation 453I rather than treatment-associated CS mutation 453L. Resistance-associated non-CS mutations (123E and 200I) were also observed in PI-resistant clinical isolates. Non-CS mutations in the frameshift-regulating site, which controls the synthesis of Gag–Pol, did not affect frameshift efficiency in dual luciferase assays. Of note, one of four HIV isolates from patients failing PI therapies without protease mutations harboured Gag mutations associated with PI resistance (123E and 436R) and reverse transcriptase inhibitor mutations conferring resistance to the backbone drug. Conclusions HIV Gag CS mutations commonly occurred in HIV isolates from patients failing PI therapies and natural polymorphisms at the same position influence their emergence. Non-CS mutations previously associated with PI resistance were also observed in clinical isolates. Gag mutations might indicate the evolution of PI resistance even in the absence of protease mutations.