The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts

• Published in: Journal of clinical virology 2008-08, Vol.42 (4), p.405-408
• Main Authors: Sista, P, Wasikowski, B, Lecocq, P, Pattery, T, Bacheler, L
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Amino Acid Substitution - genetics; Atazanavir; Atazanavir Sulfate; Biological and medical sciences; Clinically relevant resistance; Databases, Nucleic Acid; Drug Resistance, Viral; Fundamental and applied biological sciences. Psychology; HIV Protease - genetics; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 resistance; Human immunodeficiency virus 1; Human viral diseases; Humans; I50L; Infectious Disease; Infectious diseases; Medical sciences; Microbiology; Miscellaneous; Mutation, Missense; Oligopeptides - pharmacology; PI hyper-susceptibility; Predicted phenotypic resistance; Pyridines - pharmacology; Software; Viral diseases; Virology
• ISSN: 1386-6532; 1873-5967
• DOI: 10.1016/j.jcv.2008.03.023

Abstract Background The HIV-1 protease mutation I50 L causes atazanavir resistance but increases susceptibility to other PIs. Predicted phenotypic FC values were obtained from viral genotypes, using the virtual Phenotype-LM bioinformatics tool (powering vircoTYPE). Objective To evaluate I50 L's effect on susceptibility to 8 PIs, in a large genotype database. Study design I50 L containing routine clinical isolate samples in Virco's genotype database were paired with samples having like patterns (or profiles) of IAS-USA-defined primary PI mutations, but lacking I50 L. Using vircoTYPE (version 4.1), the median predicted FC for each mutational profile was determined. I50 L-associated shifts in FC were evaluated using drug-specific CCOs. Results We selected 307 and 37098 samples with and without I50 L. These corresponded to 31 mutation patterns of ≥ 3 samples each. I50 L caused resistance to atazanavir in all 31 mutation contexts, but was associated with higher susceptibility for other PIs. The largest I50 L-associated shifts in median predicted FC were: 1.2 to 42.4 (atazanavir), 10.2 to 3.2 (amprenavir), 3.3 to 0.5 (darunavir), 13 to 0.5 (indinavir), 34.9 to 1.3 (lopinavir), 22.3 to 1.3 (nelfinavir), 5.2 to 0.3 (saquinavir) and 29.9 to 5.2 (tipranavir). Conclusions The PI mutation I50 L causes clinically relevant resistance and increased susceptibility to atazanavir and other PIs respectively.