High Concordance between the Position-Specific Scoring Matrix and Geno2pheno Algorithms for Genotypic Interpretation of HIV-1 Tropism: V3 Length as the Major Cause of Disagreement

Seclén, Eduardo; Soriano, Vincent; González, María M.; Gómez, Sagrario; Thielen, Alexander; Poveda, Eva

doi:10.1128/jcm.00908-11

Cited by 19 publications

(18 citation statements)

References 10 publications

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“…In parallel, the same patients were analyzed with the TrofileES test. Previous studies have confirmed the good agreement between the phenotypic format of TrofileES and the genotyping tool Geno2Pheno on a retrospective comparison of a large study population in clinical studies (47,48). As further confirmation, we also performed a parallel analysis with TrofileES on a limited set of 20 clinical samples.…”

Section: Resultssupporting

confidence: 50%

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

et al. 2015

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dKey clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simplerto-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. The predominant virus variant in early stages of the clinical manifestation of disease, CCR5-tropic HIV, is found in approximately 80% of treatment-naive patients (1, 2). Although this number can vary for the different virus subtypes, the percentage of CXCR4-tropic HIV isolates is generally low and tends to rise with disease progression (3-6). Nevertheless, the fraction of CCR5-tropic viruses in clinical specimens continues to stay at Ͼ50% throughout the course of infection (7,8). As such, the molecular interactions between the viral envelope and the cellular chemokine receptor CCR5 were recognized as potentially attractive targets for drug development and have yielded compounds and drugs able to specifically block CCR5-tropic HIV (9-11). It is this selectivity of the inhibition of one (CCR5) and not the other (CXCR4) viral coreceptor that necessitates tropism testing prior to prescribing drugs of this particular class. Although the chemokine receptor binding site in the HIV envelope is constituted mainly by the V3 loop, the V1/V2 regions, and the C4 conserved region in the HIV protein gp120, coreceptor tropism is dictated predominantly by amino acid sequences of the V3 region (12, 13). But also sequences of other variable env regions can contribute as secondary sites to the viral tropism (14-17).Initially, all...

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Section: Resultssupporting

confidence: 50%

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

et al. 2015

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“…In general, population-based sequencing tests are less sensitive and less specific than phenotypic assays (14,29), although a few studies have shown significant concordance and similar predictive values (40,68,69). On the other hand, more sensitive deep sequencing methods for HIV-1 coreceptor tropism assays resulted in the detection of minor variants, which correlated well with both phenotypic assays (39,40,57) and virological response to maraviroc (39,40).…”

Section: Discussionmentioning

confidence: 71%

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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“…49 We found that 18% (56/304) of samples had a V3 loop length that was not the standard 35 codons ( s105 nucleotides; Table 1) and 53/56 (95%) V3 loops had a single-codon deletion and a length of 102 nucleotides. Of V3 loop length variants 7/56 (12%) and 11/56 (20%) were classified as non-R5 by ESTA and UDS, respectively, compared to …”

Section: V3 Loop Length Variationmentioning

confidence: 72%

Comparison of Genotypic and Phenotypic HIV Type 1 Tropism Assay: Results from the Screening Samples of Cenicriviroc Study 202, a Randomized Phase II Trial in Treatment-Naive Subjects

KaganRon

JohnsonErik

SiawMartin

et al. 2014

AIDS Research and Human Retroviruses

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Cenicriviroc is a once-daily oral CCR5/CCR2 antagonist in development for treatment of HIV infection. CVC Study 202 (652-2-202; NCT01338883) excluded treatment-naive subjects demonstrated to harbor non-R5 (CXCR4-tropic or dual-mixed) tropic HIV-1 by either genotypic or phenotypic tropism testing. Here we compare the results of genotypic and phenotypic tropism testing in Study 202. A total of 304 subjects screened had paired genotypic and phenotypic results. Genotypic tropism testing (GTT) incorporated triplicate population sequencing using the geno2pheno algorithm and the PSSM algorithm, followed by ultradeep sequencing (UDS) for samples with R5 results. All samples were further evaluated with a phenotypic test, the enhanced-sensitivity Trofile assay (ESTA). Concordance between GTT and ESTA was 80% and increased to 84% when only geno2-pheno was used for triplicate population sequencing. GTT (geno2pheno) classified 18% of the samples as non-R5 compared to 16% by ESTA. Only one-third of samples with non-R5 results by either test were classified as non-R5 by both tests. Median CD4( + ) cell counts were lower in patients with concordant non-R5 results by UDS and ESTA than in subjects with an R5 result by either assay ( p = 0.0004). UDS detected non-R5 virus in an additional 27/304 subjects (median 15% non-R5, interquartile range: 3.7-62%) with R5 results by ESTA. In conclusion, the geno2pheno algorithm improves concordance of GTT with a clinically validated phenotypic tropism assay as does the use of UDS. These findings provide support for recent guidelines indicating that genotypic tropism testing may be considered as an alternative to phenotypic testing.

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High Concordance between the Position-Specific Scoring Matrix and Geno2pheno Algorithms for Genotypic Interpretation of HIV-1 Tropism: V3 Length as the Major Cause of Disagreement

Cited by 19 publications

References 10 publications

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

A Diagnostic HIV-1 Tropism System Based on Sequence Relatedness

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

Comparison of Genotypic and Phenotypic HIV Type 1 Tropism Assay: Results from the Screening Samples of Cenicriviroc Study 202, a Randomized Phase II Trial in Treatment-Naive Subjects

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