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Antiviral Agents

Molecular Mechanisms of Resistance to Human Immunodeficiency Virus Type 1 with Reverse Transcriptase Mutations K65R and K65R+M184V and Their Effects on Enzyme Function and Viral Replication Capacity

Kirsten L. White, Nicolas A. Margot, Terri Wrin, Christos J. Petropoulos, Michael D. Miller, Lisa K. Naeger
Kirsten L. White
1Gilead Sciences, Foster City, California 94404
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  • For correspondence: kwhite@gilead.com
Nicolas A. Margot
1Gilead Sciences, Foster City, California 94404
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Terri Wrin
2ViroLogic, Inc., South San Francisco, California 94080
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Christos J. Petropoulos
2ViroLogic, Inc., South San Francisco, California 94080
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Michael D. Miller
1Gilead Sciences, Foster City, California 94404
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Lisa K. Naeger
1Gilead Sciences, Foster City, California 94404
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DOI: 10.1128/AAC.46.11.3437-3446.2002
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ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) resistance mutations K65R and M184V result in changes in susceptibility to several nucleoside and nucleotide RT inhibitors. K65R-containing viruses showed decreases in susceptibility to tenofovir, didanosine (ddI), abacavir, and (−)-β-d-dioxolane guanosine (DXG; the active metabolite of amdoxovir) but appeared to be fully susceptible to zidovudine and stavudine in vitro. Viruses containing the K65R and M184V mutations showed further decreases in susceptibility to ddI and abacavir but increased susceptibility to tenofovir compared to the susceptibilities of viruses with the K65R mutation. Enzymatic and viral replication analyses were undertaken to elucidate the mechanisms of altered drug susceptibilities and potential fitness defects for the K65R and K65R+M184V mutants. The relative inhibitory capacities (Ki/Km) of the active metabolites of tenofovir, ddI, and DXG were increased for the RT containing the K65R mutation compared to that for the wild-type RT, but the relative inhibitory capacity of abacavir was only minimally increased. For the mutant viruses with the K65R and M184V mutations, the increase in tenofovir susceptibility compared to that of the mutants with K65R correlated with a decrease in the tenofovir inhibitory capacity that was mediated primarily by an increased Km of dATP. The decrease in susceptibility to ddI by mutants with the K65R and M184V mutations correlated with an increase in the inhibitory capacity mediated by an increased Ki. ATP-mediated removal of carbovir as well as small increases in the inhibitory capacity of carbovir appear to contribute to the resistance of mutants with the K65R mutation and the mutants with the K65R and M184V mutations to abacavir. Finally, both the HIV-1 K65R mutant and, more notably, the HIV-1 K65R+M184V double mutant showed reduced replication capacities and reduced RT processivities in vitro, consistent with a potential fitness defect in vivo and the low prevalence of the K65R mutation among isolates from antiretroviral agent-experienced patients.

  • Copyright © 2002 American Society for Microbiology
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Molecular Mechanisms of Resistance to Human Immunodeficiency Virus Type 1 with Reverse Transcriptase Mutations K65R and K65R+M184V and Their Effects on Enzyme Function and Viral Replication Capacity
Kirsten L. White, Nicolas A. Margot, Terri Wrin, Christos J. Petropoulos, Michael D. Miller, Lisa K. Naeger
Antimicrobial Agents and Chemotherapy Nov 2002, 46 (11) 3437-3446; DOI: 10.1128/AAC.46.11.3437-3446.2002

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Molecular Mechanisms of Resistance to Human Immunodeficiency Virus Type 1 with Reverse Transcriptase Mutations K65R and K65R+M184V and Their Effects on Enzyme Function and Viral Replication Capacity
Kirsten L. White, Nicolas A. Margot, Terri Wrin, Christos J. Petropoulos, Michael D. Miller, Lisa K. Naeger
Antimicrobial Agents and Chemotherapy Nov 2002, 46 (11) 3437-3446; DOI: 10.1128/AAC.46.11.3437-3446.2002
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KEYWORDS

Anti-HIV Agents
Drug Resistance, Viral
HIV Reverse Transcriptase
HIV-1
mutation
Reverse Transcriptase Inhibitors
Virus Replication

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