The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors

• Published in: Journal of antimicrobial chemotherapy Vol. 67; no. 4; pp. 988 - 994
• Main Authors: Martinez-Cajas, Jorge L., Wainberg, Mark A., Oliveira, Maureen, Asahchop, Eugene L., Doualla-Bell, Florence, Lisovsky, Irene, Moisi, Daniela, Mendelson, Ella, Grossman, Zehava, Brenner, Bluma G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2012; Oxford Publishing Limited (England)
• Subjects: Amino Acid Substitution; Anti-HIV Agents - pharmacology; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Atazanavir Sulfate; Biological and medical sciences; Cells, Cultured; Cord blood; Corticotropin-releasing hormone; Cross-resistance; Drug resistance; Drug Resistance, Viral; Gene polymorphism; Genotype; HIV; HIV Infections - virology; HIV Protease - genetics; HIV Protease Inhibitors - pharmacology; HIV-1 - classification; HIV-1 - genetics; HIV-1 - isolation & purification; Human immunodeficiency virus; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Leukocytes (mononuclear); Leukocytes, Mononuclear - virology; Lopinavir; Lopinavir - pharmacology; Medical sciences; Mutation; Nelfinavir; Nelfinavir - pharmacology; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Polymorphism; Polymorphism, Genetic; Pressure; Protease inhibitors; Proteinase inhibitors; Pyridines - pharmacology; Tissue culture; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Cultivation; genetic diversity; antiretroviral drugs; mutations; HIV; non-B subtypes; Antiretroviral agent; Genetic variability; HIV-1 virus; Research and development; Gene; Antiviral; Genetics; Drug; Immunopathology; Treatment resistance; Typing; Enzyme; Position; Retroviridae; Genotype; AIDS; Genetic diversity; Immune deficiency; Lentivirus; Infection; Virus; Peptidases; Viral disease; Hydrolases; Human immunodeficiency virus; Mutation; Subtype; Protease inhibitor; Polymorphism
• DOI: 10.1093/jac/dkr582
• ISSN: 0305-7453; 1460-2091

Objectives Relatively little is known about the development of resistance to protease inhibitors (PIs) in non-B subtypes. In subtype B viruses, L89 is commonly found at position 89 in the HIV protease (PR) gene, whereas M89 is commonly observed as a polymorphism in other subtypes. We compared the frequencies of substitutions at position 89 in PR in tissue culture selections and in clinical databases of PI-naive and PI-experienced populations. Methods Representative subtype A/CRF01_AE (n = 2 and 3) and subtype C (n = 5) isolates were cultured in MT-2 cells and cord blood mononuclear cells (CBMCs), respectively, under increasing drug pressure with PIs, and drug resistance mutations were identified. Results The M89 natural polymorphism in non-B subtypes commonly led to the appearance of an M89T mutation in selections with atazanavir in subtypes A/AE and C, and was accompanied by other previously recognized atazanavir mutations. The M89T mutation contributed to phenotypic resistance to atazanavir and cross-resistance to lopinavir and nelfinavir, but not to other PIs. A shift from a L89 natural polymorphism to L89I/M arose in two of five subtype C selections with PIs. M89I/V/T mutations were acquired by 10%-11% of individuals harbouring non-B subtypes who were failing PI-based regimens, but were rarely observed in drug-naive persons and in patients failing non-PI-based regimens. Conclusions The M/L89 natural polymorphism present in non-B subtypes may lead to the M89T mutational pathway conferring resistance to atazanavir, lopinavir and nelfinavir.