Response to Vicriviroc in Treatment‐Experienced Subjects, as Determined by an Enhanced‐Sensitivity Coreceptor Tropism Assay: Reanalysis of AIDS Clinical Trials Group A5211

Su, Zhaohui; Gulick, Roy M.; Krambrink, Amy; Coakley, Eoin; Hughes, Michael D.; Han, Dong; Flexner, Charles; Wilkin, Timothy; Skolnik, Paul R.; Greaves, Wayne; Kuritzkes, Daniel R.; Reeves, Jacqueline D.

doi:10.1086/648090

Cited by 58 publications

(57 citation statements)

References 8 publications

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“…As a consequence, assay sensitivity (i.e., percentage of the non-R5 minority variants that can be detected consistently) has played a major role on the success of clinical trials of CCR5 antagonists (13,58,59,61,62). Here, we have consistently shown that VERITROP has a 0.3% sensitivity threshold for detecting CXCR4-using minor variants, which is similar to the sensitivity reported for the widely used ESTA (42).…”

Section: Discussionsupporting

confidence: 81%

“…The use of CCR5 antagonists in antiretroviral regimens has relied on the ability of HIV-1 tropism assays to detect viruses capable of using CXCR4 to enter the host cell (29,(58)(59)(60). As a consequence, assay sensitivity (i.e., percentage of the non-R5 minority variants that can be detected consistently) has played a major role on the success of clinical trials of CCR5 antagonists (13,58,59,61,62).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Weber

Vázquez²,

Winner³

et al. 2013

J Clin Microbiol

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Weber

Vázquez²,

Winner³

et al. 2013

J Clin Microbiol

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“…Cell-based assays for entry phenotype test either virus isolates or viruses pseudotyped by using cloned viral env genes. Phenotyping consists of infecting cells expressing CD4 and either CCR5 or CXCR4 (5,6) or inhibiting infection with antagonists of CCR5 and/or CXCR4. Alternatively, assignment of coreceptor tropism by sequence analysis has been based on sequencing of the V3 loop coding domain of the viral env gene.…”

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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“…15 A more recent publication demonstrated that a newly enhanced tropism assay would be a better screening tool for eligibility of the antagonist by identifying genetic variants below the detection limit of the original assay. 16 This example demonstrates the moving target of accuracy in this rapidly evolving field.…”

Section: Diagnostic and Drug Researchmentioning

confidence: 90%

Personalized Medicine: Understanding Probabilities and Managing Expectations

Laksman

Detsky

2010

J GEN INTERN MED

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Personalized medicine promises to represent a transformation in clinical care that will be ushered in by the unprecedented growth and development in the field of human genetics. Further examination of the scientific foundations of this new hope reveals a great number of challenges that lie ahead. While basic science research feverishly races to produce solutions, we continue to wait for the translation of deliverables. Products that have and will come to market may leave our clinical communities and systems exposed and unprepared. At each step, from basic science research to infrastructure development, a great deal of creativity and investment are required before the arsenal of more personalized tools can be assimilated into our current models of health care. This commentary seeks to share perspectives on the current status of personalized medicine from the vantage point of several potential investors, and integrate them into a common set of goals and understanding. We conclude that the stylized model of personalized medicine is more akin to a marketing tool than a literal prediction of the future.

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Response to Vicriviroc in Treatment‐Experienced Subjects, as Determined by an Enhanced‐Sensitivity Coreceptor Tropism Assay: Reanalysis of AIDS Clinical Trials Group A5211

Cited by 58 publications

References 8 publications

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism

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

Personalized Medicine: Understanding Probabilities and Managing Expectations

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