Lamivudine‐Resistant Human Immunodeficiency Virus Type 1 Variants (184V) Require Multiple Amino Acid Changes to Become Co‐Resistant to Zidovudine In Vivo

Nijhuis, Monique; Schuurman, Rob; Jong, Dorien de; Leeuwen, Remko van; Lange, Joep M. A.; Danner, Sven A.; Keulen, Wilco; Groot, Tom de; Boucher, Charles A.

doi:10.1086/514056

Cited by 96 publications

(68 citation statements)

References 33 publications

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“…In the current clinical context, 3TC is used as a component of multidrug regimens, which usually include zidovudine. Resistance to both drugs involves multiple substitutions at additional sites, which include site 210 in addition to changes seen under single-drug therapy at 184 and 215 (15,22): although not well understood, the fitness differences between the different combinations are almost certainly smaller than the fitness differences observed here between M184V and M184I. In addition, multiple mutants will also occur at a lower frequency than single mutants.…”

Section: Discussionmentioning

confidence: 87%

Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection

Frost

Nijhuis

Schuurman

et al. 2000

J Virol

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152

109

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Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4؉ counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0.2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.Resistance to the reverse transcriptase (RT) inhibitor lamivudine (3TC) involves mutations at one residue in RT, methionine (ATG) position 184 (3, 29). Typically, after about 2 weeks of 3TC monotherapy, isoleucine (ATA) appears at this position. Although this substitution confers a several-hundredfold increase in the 50% inhibitory concentration relative to the wild type, it also dramatically reduces the replication rate of the virus by reducing the processivity of the enzyme (1). After 8 to 20 weeks, isoleucine is replaced by valine (GTG), which also confers drug resistance but has less of an impact on the processivity of RT, such that in the absence of drug, the valine mutant has a fitness intermediate to that of wild type and the isoleucine mutant in vitro.The pattern of evolution of drug resistance to 3TC, with the initial appearance of the M184I mutant, followed by the replacement of the fitter M184V mutant, has been explained in terms of a balance between mutation and selection (26). In human immunodeficiency virus (HIV), G-to-A mutations are more common than A-to-G mutations and result in a higher production rate of M184I mutants (13,17). Based on the classical population genetics result that the frequency of a deleterious mutation reflects a balance between mutation and selection (9), this mutational bias towards A must be large enough to overcome the higher fitness of M184V in order to result in M184I mutants being present at higher frequencies than M...

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Section: Discussionmentioning

confidence: 87%

Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection

Frost

Nijhuis

Schuurman

et al. 2000

J Virol

Self Cite

152

109

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show abstract

“…Treatment of HIV-1-infected patients with (Ϫ)2=,3=-dideoxy-3=-thiacytidine (lamivudine, 3TC) or (Ϫ)2=, 3=-dideoxy-5-fluoro-3=-thiacytidine (emtricitabine, FTC) leads to selection of the M184I mutation in RT, which is rapidly replaced with M184V (7,25,52,57). The M184V mutation is a potent suppressor of AZT resistance conferred by TAMs (7,30,40,57), and this suppressor activity is thought to contribute to the beneficial effects of therapies that include 3TC or FTC in combination with other nucleoside RT inhibitors (19,30,40,44,56).Methionine 184 is part of the YMDD signature motif that makes up the polymerase active site of HIV-1 RT and lies near the binding sites for the primer terminus and the incoming deoxynucleoside triphosphate (dNTP) (28,31). M184I is usually selected first during therapy with 3TC or FTC, and structural studies to investigate the molecular mechanism of drug resistance have focused on RT containing this mutation.…”

mentioning

confidence: 99%

A Role of Template Cleavage in Reduced Excision of Chain-Terminating Nucleotides by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing the M184V Mutation

Acosta-Hoyos

Matsuura

Meyer

et al. 2012

J Virol

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Resistance to nucleoside reverse transcriptase (RT) inhibitors is conferred on human immunodeficiency virus type 1 through thymidine analogue resistance mutations (TAMs) that increase the ability of RT to excise chain-terminating nucleotides after they have been incorporated. The RT mutation M184V is a potent suppressor of TAMs. In RT containing TAMs, the addition of M184V suppressed the excision of 3′-deoxy-3′-azidothymidine monophosphate (AZTMP) to a greater extent on an RNA template than on a DNA template with the same sequence. The catalytically inactive RNase H mutation E478Q abolished this difference. The reduction in excision activity was similar with either ATP or pyrophosphate as the acceptor substrate. Decreased excision of AZTMP was associated with increased cleavage of the RNA template at position −7 relative to the primer terminus, which led to increased primer-template dissociation. Whether M184V was present or not, RT did not initially bind at the −7 cleavage site. Cleavage at the initial site was followed by RT dissociation and rebinding at the −7 cleavage site, and the dissociation and rebinding were enhanced when the M184V mutation was present. In contrast to the effect of M184V, the K65R mutation suppressed the excision activity of RT to the same extent on either an RNA or a DNA template and did not alter the RNase H cleavage pattern. Based on these results, we propose that enhanced RNase H cleavage near the primer terminus plays a role in M184V suppression of AZT resistance, while K65R suppression occurs through a different mechanism.

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“…20 The increase in the number of mutations required to confer phenotypic resistance to zidovudine in the presence of lamivudine has been proposed as a mechanism for this observation. 23 Although the trial did not have power to detect additional clinical benefit between the lamivudine and the lamivudine plus loviride arms, the effect of loviride in our study population was marginal. The CD4 and viral-load data indicated an incremental benefit in the initial response to treatment for the lamivudine plus loviride arm over the lamivudine arm in the overall population.…”

Section: Discussionmentioning

confidence: 81%

Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial

1997

The Lancet

226

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Lamivudine‐Resistant Human Immunodeficiency Virus Type 1 Variants (184V) Require Multiple Amino Acid Changes to Become Co‐Resistant to Zidovudine In Vivo

Cited by 96 publications

References 33 publications

Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection

Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection

A Role of Template Cleavage in Reduced Excision of Chain-Terminating Nucleotides by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing the M184V Mutation

Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial

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