Population-Based Sequencing of the V3-loop Can Predict the Virological Response to Maraviroc in Treatment-Naive Patients of the MERIT Trial

McGovern, Rachel A.; Thielen, Alexander; Portsmouth, Simon; Mo, Theresa; Dong, Winnie; Woods, Conan K.; Zhong, Xiaoyin; Brumme, Chanson J.; Chapman, Douglass; Lewis, Marilyn; James, Ian; Heera, Jayvant; Valdez, Hernán; Harrigan, P. Richard

doi:10.1097/qai.0b013e31826249cf

Cited by 49 publications

(40 citation statements)

References 20 publications

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“…Of the clonal model 5.75% FPR was first selected as this is the only validated FPR with clinical studies. 31,32 ''Recommendations from the European Consensus Group on the clinical management of HIV-1 tropism testing (10% FPR)'' 3 was selected for the second batch of analysis. The third set of analysis used the clinical model of G2P (FPR = 10%) 10,33 with the input of patient clinical parameters including viral load and CD4 and CD8 cell counts.…”

Section: Tropism Genotyping By G2p Webpssm and Cn Rulesmentioning

confidence: 99%

Determination of the High Prevalence of Dual/Mixed- or X4-Tropism Among HIV Type 1 CRF01_AE in Hong Kong by Genotyping and Phenotyping Methods

Chen

Wong

et al. 2013

AIDS Research and Human Retroviruses

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In Hong Kong, the CCR5 antagonist has recently been introduced into salvage therapy for multiclass drug-resistant HIV-1-infected patients. Coreceptor usage must be determined prior to the usage of the CCR5 antagonist, which does not inhibit X4-tropic viruses. This study aimed to determine the tropism prevalence for HIV-1 subtypes B and CRF01_AE in Hong Kong. In addition, a modified promoter-PCR phenotypic assay was used to validate the genotypic tropism prediction on CRF01_AE. One hundred and five subtype B and 98 CRF01_AE antiretroviral-naive patients were recruited for this study. The viral env V3 region isolated from the patients was sequenced and analyzed by Geno2pheno (FPR=5.75% or 10%, Clonal or Clinical), position-specific scoring matrix (WebPSSM, x4r5 subtype B matrix), and the combination of 11/25 and net charge rules. Fifteen concordant and 22 discordant tropism genotyped CRF01_AE samples were further phenotyped by either enhanced sensitivity Trofile assay or an optimized promoter-PCR phenotypic assay. The prevalence of Dual/Mixed- or X4-tropic virus in antiretroviral-naive subtype CRF01_AE was 39.1%, which was significantly higher than subtype B (p<0.05), regardless of the choices of genotypic algorithms. Our phenotypic data proposed that a better genotypic tropism prediction for HIV-1 CRF01_AE would be using both Geno2pheno (FPR=10%, Clonal) and WebPSSM (x4r5 subtype B matrix) algorithms in combination. The sensitivity and specificity for this combination were 88.9% and 89.3%, respectively. The comparatively high prevalence of Dual/Mixed- or X4-tropic virus in CRF01_AE demonstrated the need for special attention to future treatment strategies.

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Section: Tropism Genotyping By G2p Webpssm and Cn Rulesmentioning

confidence: 99%

Determination of the High Prevalence of Dual/Mixed- or X4-Tropism Among HIV Type 1 CRF01_AE in Hong Kong by Genotyping and Phenotyping Methods

Chen

Wong

et al. 2013

AIDS Research and Human Retroviruses

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“…The position-specific scoring matrix (PSSM) analyzes the entire V3 sequence and predicts X4 variants based on a scoring of the probability of the amino acid at each position being overrepresented among X4 sequences versus R5 sequences (10). The Geno2Pheno (G2P) algorithm (11) also analyzes the entire V3 sequence and provides a quantitative score (false-positive rate [FPR]) representing the probability of falsely predicting an R5 variant as an X4 variant; the validity of this approach has been assessed in several clinical trials (12)(13)(14)(15)(16). G2P has been widely used in research and clinical settings, but it requires a preset FPR cutoff to call X4 variants.…”

mentioning

confidence: 99%

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Zhou

Bednar

Sturdevant

et al. 2016

J Virol

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HIV-1 requires the CD4 receptor and a coreceptor (CCR5 [R5 phenotype] or CXCR4 [X4 phenotype]) to enter cells. Coreceptor tropism can be assessed by either phenotypic or genotypic analysis, the latter using bioinformatics algorithms to predict tropism based on the env V3 sequence. We used the Primer ID sequencing strategy with the MiSeq sequencing platform to reveal the structure of viral populations in the V1/V2 and C2/V3 regions of the HIV-1 env gene in 30 late-stage and 6 early-stage subjects. We also used endpoint dilution PCR followed by cloning of env genes to create pseudotyped virus to explore the link between genotypic predictions and phenotypic assessment of coreceptor usage. We found out that the most stringently sequence-based calls of X4 variants (Geno2Pheno false-positive rate [FPR] of <2%) formed distinct lineages within the viral population, and these were detected in 24 of 30 late-stage samples (80%), which was significantly higher than what has been seen previously by using other approaches. Non-X4 lineages were not skewed toward lower FPR scores in X4-containing populations. Phenotypic assays showed that variants with an intermediate FPR (2 to 20%) could be either X4/dual-tropic or R5 variants, although the X4 variants made up only about 25% of the lineages with an FPR of <10%, and these variants carried a distinctive sequence change. Phylogenetic analysis of both the V1/V2 and C2/V3 regions showed evidence of recombination within but very little recombination between the X4 and R5 lineages, suggesting that these populations are genetically isolated. IMPORTANCEPrimer ID sequencing provides a novel approach to study genetic structures of viral populations. X4 variants may be more prevalent than previously reported when assessed by using next-generation sequencing (NGS) and with a greater depth of sampling than single-genome amplification (SGA). Phylogenetic analysis to identify lineages of sequences with intermediate FPR values may provide additional information for accurately predicting X4 variants by using V3 sequences. Limited recombination occurs between X4 and R5 lineages, suggesting that X4 and R5 variants are genetically isolated and may be replicating in different cell types or that X4/R5 recombinants have reduced fitness. H uman immunodeficiency virus type 1 (HIV-1) requires the CD4 receptor and a coreceptor to infect host cells. Entry is mediated by the viral envelope protein (Env), which is processed to give two associated subunits, gp120 and gp41, that assemble into a trimeric structure embedded in the viral envelope/membrane. The binding of gp120 to CD4 triggers a structural change that exposes its variable region 3 (V3) loop, which is part of the coreceptor domain (1, 2). The majority of transmitted/founder (T/F) viruses and viruses isolated from the clinically latent stage in HIV-infected subjects use CCR5 as the coreceptor, making the virus CCR5 tropic (or an R5 virus). The virus can evolve to use CXCR4 (CXCR4 tropic [or an X4 virus]), and viruses that have switched core...

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“…A retrospective study evaluated genotypic tropism testing using stored plasma samples collected in the maraviroc trials and found that it was comparable to the original Trofile assay in predicting virological outcomes in treatment-experienced patients [38 ]. These authors drew the same conclusions in a study of treatmentnaive patients [39]. Genotypic tropism testing is also possible from proviral DNA, indicating a use in patients with a suppressed viral load, who are seeking to switch treatment for tolerability reasons [40,41].…”

Section: Tropism Testingmentioning

confidence: 95%

Genotypic resistance testing in routine clinical care

Dunn

Coughlin²,

Cane³

2011

Current Opinion in HIV and AIDS

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Population-Based Sequencing of the V3-loop Can Predict the Virological Response to Maraviroc in Treatment-Naive Patients of the MERIT Trial

Abstract: The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.

Cited by 49 publications

References 20 publications

Determination of the High Prevalence of Dual/Mixed- or X4-Tropism Among HIV Type 1 CRF01_AE in Hong Kong by Genotyping and Phenotyping Methods

Determination of the High Prevalence of Dual/Mixed- or X4-Tropism Among HIV Type 1 CRF01_AE in Hong Kong by Genotyping and Phenotyping Methods

Deep Sequencing of the HIV-1 env Gene Reveals Discrete X4 Lineages and Linkage Disequilibrium between X4 and R5 Viruses in the V1/V2 and V3 Variable Regions

Genotypic resistance testing in routine clinical care

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