title: The human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor resistance mutation I132M confers hypersensitivity to nucleoside analogs.
abstract: We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity.
authors.affiliation: Division of Infectious Diseases, University of Pittsburgh School of Medicine, 817B Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261, USA. ambrosez@dom.pitt.edu
authors.forename: Zandrea
authors.initials: Z
authors.lastname: Ambrose
authors.forename: Brian D
authors.initials: BD
authors.lastname: Herman
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Sheen
authors.forename: Shannon
authors.initials: S
authors.lastname: Zelina
authors.forename: Katie L
authors.initials: KL
authors.lastname: Moore
authors.forename: Gilda
authors.initials: G
authors.lastname: Tachedjian
authors.forename: Dwight V
authors.initials: DV
authors.lastname: Nissley
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sluis-Cremer
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D020008:Delavirdine / Q000494:pharmacology; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D019259:Lamivudine / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D019829:Nevirapine / Q000494:pharmacology; D063065:Organophosphonates / Q000494:pharmacology; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D019829:Nevirapine; D000068698:Tenofovir; D020008:Delavirdine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000225:Adenine