title: Mutations in human immunodeficiency virus type 1 reverse transcriptase that make it sensitive to degradation by the viral protease in virions are selected against in patients.
abstract: Mutations in the thumb subdomain of reverse transcriptase (RT) of HIV-1 can cause this enzyme to be degraded in virions by the viral protease (PR). Many of these mutations confer a temperature-sensitive phenotype on RT and viral replication. The degradation of RT by PR appears to take place after Gag-Pol has been processed. We show here that mutations in other parts of RT, including the RNase H domain, can make RT PR-sensitive and temperature-sensitive. These data explain why some mutations in the RNase H domain, which had little or no effect on the polymerase activity of purified recombinant RT, had a profound effect on viral titer. Because the PR-sensitive phenotype significantly reduced viral titer, we previously suggested that these mutations would be selected against in patients. We also show that RT mutations that are known to confer a temperature sensitive phenotype are rarely found in the Stanford database.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Dunn
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Jane McWilliams
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. Electronic address: hughesst@mail.nih.gov.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
mesh_terms: D002460:Cell Line; D016333:HIV Protease / Q000378:metabolism*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D006868:Hydrolysis; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D012641:Selection, Genetic; D019562:Viral Load
chemical_list: D050505:Mutant Proteins; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Gag-Pol; HIV; Protease; RNase H; RT; Temperature sensitive