In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor

• Published in: Antiviral research Vol. 70; no. 2; pp. 66 - 74
• Main Authors: Sato, Akihiko, Hammond, Jennifer, Alexander, Therese N., Graham, Joanne P., Binford, Susan, Sugita, Ken-ichi, Sugimoto, Hirohiko, Fujiwara, Tamio, Patick, Amy K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-06-2006; Elsevier
• Subjects: Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Capravirine; Drug Resistance, Viral - genetics; HeLa Cells; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - genetics; HIV-1 - enzymology; HIV-1 - genetics; Human immunodeficiency virus 1; Human viral diseases; Humans; Imidazoles - pharmacology; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Medical sciences; Mutagenesis, Site-Directed; Mutation; Nonnucleoside reverse transcriptase inhibitor; Pharmacology. Drug treatments; Resistance; Reverse Transcriptase Inhibitors - pharmacology; Sequence Analysis, DNA; Sulfur Compounds; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Nonnucleoside reverse transcriptase inhibitor; Resistance; Capravirine; HIV; Immunopathology; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Transferases; Non nucleoside compound; Retroviridae; AIDS; Immune deficiency; Lentivirus; In vitro; Infection; Virus; Nucleotidyltransferases; Viral disease; Reverse transcriptase inhibitor; Antiviral; Human immunodeficiency virus; Mutation
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2006.01.001

Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC
50 values ranging from 0.7 to 10.3
nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4–5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.