Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors

Charpentier, Charlotte; Dwyer, Dominic E.; Mammano, Fabrizio; Lecossier, Denise; Clavel, François; Hance, Allan J.

doi:10.1128/jvi.78.8.4234-4247.2004

Cited by 79 publications

(58 citation statements)

References 58 publications

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“…Previous studies have found that viral populations expressing different resistance profiles, including those with suboptimal drug resistance, can continue to replicate in "sanctuary sites" (7,15,40,43,54,55). It is noteworthy that treatment changes may influence the repertoire of resistant viruses available to participate in recombination events.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment

Nora

Charpentier

Tenaillon

et al. 2007

J Virol

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115

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Viral recombination has been postulated to play two roles in the development of human immunodeficiency virus (HIV) resistance to antiretroviral drugs. First, recombination has the capacity to associate resistance mutations expressed by distinct viruses, thereby contributing to the development of viruses with improved drug resistance. In addition, recombination could preserve diversity in regions outside those subject to strong selective pressure. In this study, we sought direct evidence for the occurrence of these processes in vivo by evaluating clonal virus populations obtained from the same patient before and after a treatment change that, while unsuccessful in controlling viral replication, led to the emergence of viruses expressing a different profile of resistance mutations. Phylogenetic studies supported the conclusion that the genotype arising after the treatment change resulted from the emergence of recombinant viruses carrying previously existing resistance mutations in novel combinations, whereas alternative explanations, including convergent evolution, were not consistent with observed genotypic changes. Despite evidence for a strong loss of genetic diversity in genomic regions coding for the protease and reverse transcriptase, diversity in regions coding for Gag and envelope was considerably higher, and recombination between the emerging viruses expressing the new pattern of resistance mutations and viral quasispecies in the previously dominant population contributed to this preservation of diversity in the envelope gene. These findings emphasize that recombination can participate in the adaptation of HIV to changing selective pressure, both by generating novel combinations of resistance mutations and by maintaining diversity in genomic regions outside those implicated in a selective sweep.

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Section: Discussionmentioning

confidence: 99%

Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment

Nora

Charpentier

Tenaillon

et al. 2007

J Virol

Self Cite

115

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“…Preliminary evidence suggests that minor drug-resistant variants which may be missed by standard genotyping can lead to the failure of subsequent treatment regimens (6,31,33). Clearly, there must be a threshold level below which the risk of failure declines to that of drug-naïve patients.…”

Section: Discussionmentioning

confidence: 99%

Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis

et al. 2005

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To investigate the extent to which drug resistance mutations are missed by standard genotyping methods, we analyzed the same plasma samples from 26 patients with suspected multidrug-resistant human immunodeficiency virus type 1 by using a newly developed single-genome sequencing technique and compared it to standard genotype analysis. Plasma samples were obtained from patients with prior exposure to at least two antiretroviral drug classes and who were on a failing antiretroviral regimen. Standard genotypes were obtained by reverse transcriptase (RT)-PCR and sequencing of the bulk PCR product. For single-genome sequencing, cDNA derived from plasma RNA was serially diluted to 1 copy per reaction, and a region encompassing p6, protease, and a portion of RT was amplified and sequenced. Sequences from 15 to 46 single viral genomes were obtained from each plasma sample. Drug resistance mutations identified by single-genome sequencing were not detected by standard genotype analysis in 24 of the 26 patients studied. Mutations present in less than 10% of single genomes were almost never detected in standard genotypes (1 of 86). Similarly, mutations present in 10 to 35% of single genomes were detected only 25% of the time in standard genotypes. For example, in one patient, 10 mutations identified by single-genome sequencing and conferring resistance to protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were not detected by standard genotyping methods. Each of these mutations was present in 5 to 20% of the 20 genomes analyzed; 15% of the genomes in this sample contained linked PI mutations, none of which were present in the standard genotype. In another patient sample, 33% of genomes contained five linked NNRTI resistance mutations, none of which were detected by standard genotype analysis. These findings illustrate the inadequacy of the standard genotype for detecting low-frequency drug resistance mutations. In addition to having greater sensitivity, single-genome sequencing identifies linked mutations that confer high-level drug resistance. Such linkage cannot be detected by standard genotype analysis.

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“…However, it is still not clear to which extent infection of new cells occurs during the phase of viral decay after initiation of suppressive ART, and whether viral replication can lead to the early selection of drugresistant viruses. When treatment failure occurs after a period of undetectable viremia, minority drug-resistant quasispecies can emerge as the major viral population [Metzner et al, 2003;Charpentier et al, 2004;Roquebert et al, 2006;Svedhem et al, 2007]. These variants can either be pre-existing or evolve in the setting of incomplete viral suppression.…”

Section: Introductionmentioning

confidence: 99%

Selection of drug‐resistant HIV‐1 during the early phase of viral decay is uncommon in treatment‐naïve patients initiated on a three‐ or four‐drug antiretroviral regimen including lamivudine

Bergroth¹,

Ekici²,

Gisslén³

et al. 2008

Journal of Medical Virology

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Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n ¼ 43), triple (n ¼ 14) or dual (n ¼ 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or fourdrug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine þ PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

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Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors

Cited by 79 publications

References 58 publications

Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment

Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment

Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis

Selection of drug‐resistant HIV‐1 during the early phase of viral decay is uncommon in treatment‐naïve patients initiated on a three‐ or four‐drug antiretroviral regimen including lamivudine

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