Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling

Vermeiren, Hans; Craenenbroeck, Elke Van; Alen, P.; Bacheler, Lee T.; Picchio, Gastón; Lecocq, Pierre

doi:10.1016/j.jviromet.2007.05.009

Cited by 88 publications

(94 citation statements)

References 21 publications

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“…HIV-1 resistance to PI, NRTI, NNRTI, and INI can be determined using (i) indirect methods based on the detection of specific amino acid substitutions (due to underlying nucleotide mutations) in the respective coding regions previously associated with resistance to specific antiretroviral drugs (i.e., genotyping) (6,9,10), (ii) more direct methods that test the ability of a patient-derived virus to replicate in the presence of antiretroviral drugs in a cell-based assay (i.e., phenotyping) (11)(12)(13), or (iii) a combination of the two approaches that takes advantage of a large database in order to infer the level of HIV-1 drug resistance based on genotyping and its relationship with matched phenotypic data (14). Similarly, since treatment with CCR5 antagonists requires prior knowledge of the HIV-1 coreceptor tropism in the patient, i.e., CCR5-or CXCR4-tropic viruses (R5 and X4, respectively), dual tropism (R5/X4), or a mixture of both R5 and X4 viruses (7,15), a multitude of phenotypic and genotypic approaches to determine HIV-1 coreceptor tropism have been developed (8,16,17).…”

mentioning

confidence: 99%

Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism

Gibson

Meyer

Winner

et al. 2014

Antimicrob Agents Chemother

111

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mentioning

confidence: 99%

Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism

Gibson

Meyer

Winner

et al. 2014

Antimicrob Agents Chemother

111

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“…To minimize bias that would result from overrepresenting highly similar viruses, we excluded 200 redundant viruses-defined as viruses obtained from the same person with the same mutations at the following PI resistance positions: positions 30,32,46,47,54,76,82,84, and 90 (20). Because the presence of mixtures at influential drug resistance positions may confound genotype-phenotype correlations, we excluded 472 viruses with sequences containing electrophoretic mixtures at these protease positions.…”

mentioning

confidence: 99%

HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

Rhee

Taylor

Fessel

et al. 2010

Antimicrob Agents Chemother

185

205

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The effects of many protease inhibitor (PI)-selected mutations on the susceptibility to individual PIs are unknown. We analyzed in vitro susceptibility test results on 2,725 HIV-1 protease isolates. More than 2,400 isolates had been tested for susceptibility to fosamprenavir, indinavir, nelfinavir, and saquinavir; 2,130 isolates had been tested for susceptibility to lopinavir; 1,644 isolates had been tested for susceptibility to atazanavir; 1,265 isolates had been tested for susceptibility to tipranavir; and 642 isolates had been tested for susceptibility to darunavir. We applied least-angle regression (LARS) to the 200 most common mutations in the data set and identified a set of 46 mutations associated with decreased PI susceptibility of which 40 were not polymorphic in the eight most common HIV-1 group M subtypes. We then used least-squares regression to ascertain the relative contribution of each of these 46 mutations. The median number of mutations associated with decreased susceptibility to each PI was 28 (range, 19 to 32), and the median number of mutations associated with increased susceptibility to each PI was 2.5 (range, 1 to 8). Of the mutations with the greatest effect on PI susceptibility, I84AV was associated with decreased susceptibility to eight PIs; V32I, G48V, I54ALMSTV, V82F, and L90M were associated with decreased susceptibility to six to seven PIs; I47A, G48M, I50V, L76V, V82ST, and N88S were associated with decreased susceptibility to four to five PIs; and D30N, I50L, and V82AL were associated with decreased susceptibility to fewer than four PIs. This study underscores the greater impact of nonpolymorphic mutations compared with polymorphic mutations on decreased PI susceptibility and provides a comprehensive quantitative assessment of the effects of individual mutations on susceptibility to the eight clinically available PIs.HIV-1 protease inhibitors (PIs) are the mainstays of salvage therapy. As the number of licensed PIs has increased, it has become important to identify whether and how each PI-selected mutation affects cross-resistance to each of the other PIs. In a previous study (41), we previously applied several data mining approaches to assess associations between HIV-1 protease genotype and phenotype test results for the first-generation PIs: amprenavir (APV), the active component of the prodrug fosamprenavir (FPV), atazanavir (ATV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), and saquinavir (SQV). Specifically, we used a data set containing about 300 susceptibility results for ATV, 500 for LPV, and 800 for FPV, IDV, NFV, and SQV (41). We used a predefined list of PIselected mutations in this previous study to reduce the number of independent variables influencing PI susceptibility.Here we analyze a data set that contains between 1,600 and 2,600 isolates tested for susceptibility to the first-generation PIs and about 600 and 1,200 isolates tested for susceptibility to darunavir (DRV) and tipranavir (TPV), respectively. We use two regression methods in tandem: one to identi...

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“…The Ile-to-Val substitution at residue 50 (I50V) is the signature resistance mutation in patients failing APV and DRV therapy (11)(12)(13)(14). On the other hand, mutation to Leu at this position (I50L) is observed in patients failing ATV therapy (15,16).…”

mentioning

confidence: 99%

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

Mittal

Bandaranayake

King

et al. 2013

J Virol

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Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions.

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Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling

Cited by 88 publications

References 21 publications

Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism

Sensitive Deep-Sequencing-Based HIV-1 Genotyping Assay To Simultaneously Determine Susceptibility to Protease, Reverse Transcriptase, Integrase, and Maturation Inhibitors, as Well as HIV-1 Coreceptor Tropism

HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

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