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HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRRF01_AE and CRF02_AG

(2013) PLOS ONE. 8(5).
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Abstract
Background: Human Immunodeficiency virus type-1 (HIV) entry into target cells involves binding of the viral envelope (Env) to CD4 and a coreceptor, mainly CCR5 or CXCR4. The only currently licensed HIV entry inhibitor, maraviroc, targets CCR5, and the presence of CXCX4-using strains must be excluded prior to treatment. Co-receptor usage can be assessed by phenotypic assays or through genotypic prediction. Here we compared the performance of a phenotypic Env-Recombinant Viral Assay (RVA) to the two most widely used genotypic prediction algorithms, Geno2Pheno([coreceptor]) and webPSSM. Methods: Co-receptor tropism of samples from 73 subtype B and 219 non-B infections was measured phenotypically using a luciferase-tagged, NL4-3-based, RVA targeting Env. In parallel, tropism was inferred genotypically from the corresponding V3-loop sequences using Geno2Pheno([coreceptor]) (5-20% FPR) and webPSSM-R5X4. For discordant samples, phenotypic outcome was retested using co-receptor antagonists or the validated Trofile (R) Enhanced-Sensitivity-Tropism-Assay. Results: The lower detection limit of the RVA was 2.5% and 5% for X4 and R5 minority variants respectively. A phenotype/genotype result was obtained for 210 samples. Overall, concordance of phenotypic results with Geno2Pheno([coreceptor]) was 85.2% and concordance with webPSSM was 79.5%. For subtype B, concordance with Geno2pheno([coreceptor]) was 94.4% and concordance with webPSSM was 79.6%. High concordance of genotypic tools with phenotypic outcome was seen for subtype C (90% for both tools). Main discordances involved CRF01_AE and CRF02_AG for both algorithms (CRF01_AE: 35.9% discordances with Geno2Pheno([coreceptor]) and 28.2% with webPSSM; CRF02_AG: 20.7% for both algorithms). Genotypic prediction overestimated CXCR4-usage for both CRFs. For webPSSM, 40% discordance was observed for subtype A. Conclusions: Phenotypic assays remain the most accurate for most non-B subtypes and new subtype-specific rules should be developed for non-B subtypes, as research studies more and more draw conclusions from genotypically-inferred tropism, and to avoid unnecessarily precluding patients with limited treatment options from receiving maraviroc or other entry inhibitors.
Keywords
CHEMOKINE RECEPTORS, CCR5 ANTAGONISTS, BIOINFORMATIC TOOLS, V3 LOOP, CORECEPTOR USAGE, T-CELL-LINE, IMMUNODEFICIENCY-VIRUS TYPE-1, N-LINKED GLYCOSYLATION, DRUG-RESISTANCE, INFECTION

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Chicago
Mulinge, Martin, Morgane Lemaire, Jean-Yves Servais, Arkadiusz Rybicki, Daniel Struck, Eveline Santos da Silva, Chris Verhofstede, et al. 2013. “HIV-1 Tropism Determination Using a Phenotypic Env Recombinant Viral Assay Highlights Overestimation of CXCR4-usage by Genotypic Prediction Algorithms for CRRF01_AE and CRF02_AG.” Plos One 8 (5).
APA
Mulinge, M., Lemaire, M., Servais, J.-Y., Rybicki, A., Struck, D., da Silva, E. S., Verhofstede, C., et al. (2013). HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRRF01_AE and CRF02_AG. PLOS ONE, 8(5).
Vancouver
1.
Mulinge M, Lemaire M, Servais J-Y, Rybicki A, Struck D, da Silva ES, et al. HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRRF01_AE and CRF02_AG. PLOS ONE. 2013;8(5).
MLA
Mulinge, Martin, Morgane Lemaire, Jean-Yves Servais, et al. “HIV-1 Tropism Determination Using a Phenotypic Env Recombinant Viral Assay Highlights Overestimation of CXCR4-usage by Genotypic Prediction Algorithms for CRRF01_AE and CRF02_AG.” PLOS ONE 8.5 (2013): n. pag. Print.
@article{4270741,
  abstract     = {Background: Human Immunodeficiency virus type-1 (HIV) entry into target cells involves binding of the viral envelope (Env) to CD4 and a coreceptor, mainly CCR5 or CXCR4. The only currently licensed HIV entry inhibitor, maraviroc, targets CCR5, and the presence of CXCX4-using strains must be excluded prior to treatment. Co-receptor usage can be assessed by phenotypic assays or through genotypic prediction. Here we compared the performance of a phenotypic Env-Recombinant Viral Assay (RVA) to the two most widely used genotypic prediction algorithms, Geno2Pheno([coreceptor]) and webPSSM.
Methods: Co-receptor tropism of samples from 73 subtype B and 219 non-B infections was measured phenotypically using a luciferase-tagged, NL4-3-based, RVA targeting Env. In parallel, tropism was inferred genotypically from the corresponding V3-loop sequences using Geno2Pheno([coreceptor]) (5-20\% FPR) and webPSSM-R5X4. For discordant samples, phenotypic outcome was retested using co-receptor antagonists or the validated Trofile (R) Enhanced-Sensitivity-Tropism-Assay.
Results: The lower detection limit of the RVA was 2.5\% and 5\% for X4 and R5 minority variants respectively. A phenotype/genotype result was obtained for 210 samples. Overall, concordance of phenotypic results with Geno2Pheno([coreceptor]) was 85.2\% and concordance with webPSSM was 79.5\%. For subtype B, concordance with Geno2pheno([coreceptor]) was 94.4\% and concordance with webPSSM was 79.6\%. High concordance of genotypic tools with phenotypic outcome was seen for subtype C (90\% for both tools). Main discordances involved CRF01\_AE and CRF02\_AG for both algorithms (CRF01\_AE: 35.9\% discordances with Geno2Pheno([coreceptor]) and 28.2\% with webPSSM; CRF02\_AG: 20.7\% for both algorithms). Genotypic prediction overestimated CXCR4-usage for both CRFs. For webPSSM, 40\% discordance was observed for subtype A.
Conclusions: Phenotypic assays remain the most accurate for most non-B subtypes and new subtype-specific rules should be developed for non-B subtypes, as research studies more and more draw conclusions from genotypically-inferred tropism, and to avoid unnecessarily precluding patients with limited treatment options from receiving maraviroc or other entry inhibitors.},
  articleno    = {e60566},
  author       = {Mulinge, Martin and Lemaire, Morgane and Servais, Jean-Yves and Rybicki, Arkadiusz and Struck, Daniel and da Silva, Eveline Santos and Verhofstede, Chris and Lie, Yolanda and Seguin-Devaux, Carole and Schmit, Jean-Claude and Perez Bercoff, Daniele},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  language     = {eng},
  number       = {5},
  pages        = {13},
  title        = {HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRRF01\_AE and CRF02\_AG},
  url          = {http://dx.doi.org/10.1371/journal.pone.0060566},
  volume       = {8},
  year         = {2013},
}

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