title: In vitro hypersusceptibility of human immunodeficiency virus type 1 subtype C protease to lopinavir.
abstract: In order to characterize the impact of genetic polymorphisms on the susceptibility of subtype C strains of human immunodeficiency virus type 1 to protease inhibitors (PIs), a subtype B protease that originated from an infectious clone was modified through site-directed mutagenesis to include the amino acid residue signatures of subtype C viruses (I15V, M36I, R41K, H69K, L89 M) with (clone C6) or without (clone C5) an I93L polymorphism present as a molecular signature of the worldwide subtype C protease. Their susceptibilities to commercially available PIs were measured by a recombinant virus phenotyping assay. We could not detect any differences in the 50% inhibitory concentration (IC(50)s) of amprenavir, indinavir, ritonavir, saquinavir, and nelfinavir for the clones analyzed. However, we did observe hypersusceptibility to lopinavir solely in clone C6, which includes the I93L substitution (a 2.6-fold decrease in the IC(50) compared to that for the subtype B reference strain). The same phenotypic behavior was observed for 11 Brazilian and South African clinical isolates tested, in which only subtype C isolates carrying the I93L mutation presented significant hypersusceptibility to lopinavir.
authors.affiliation: Departamento de Genética, Universidade Federal do Rio de Janeiro, CCS, Bloco A, Cidade Universitária, Ilha do Fundão, 21944-970 Rio de Janeiro, RJ, Brazil.
authors.forename: Luis M F
authors.initials: LM
authors.lastname: Gonzalez
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Brindeiro
authors.forename: Michelle
authors.initials: M
authors.lastname: Tarin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Calazans
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Soares
authors.forename: Sharon
authors.initials: S
authors.lastname: Cassol
authors.forename: Amilcar
authors.initials: A
authors.lastname: Tanuri
mesh_terms: D000595:Amino Acid Sequence; D001938:Brazil; D003001:Cloning, Molecular; D016333:HIV Protease / Q000187:drug effects* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D061466:Lopinavir; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013019:South Africa
chemical_list: D017320:HIV Protease Inhibitors; D007527:Isoenzymes; D011744:Pyrimidinones; D012367:RNA, Viral; D061466:Lopinavir; D016333:HIV Protease