Performance of Geno2Pheno[coreceptor] to infer coreceptor use in human immunodeficiency virus type 1 (HIV-1) subtype A

• Published in: Journal of clinical virology Vol. 111; pp. 12 - 18
• Main Authors: Vicenti, Ilaria, Lai, Alessia, Giannini, Alessia, Boccuto, Adele, Dragoni, Filippo, Saladini, Francesco, Zazzi, Maurizio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2019
• Subjects: Algorithms; CCR5 Receptor Antagonists - therapeutic use; Coreceptor usage; Genotype; High-Throughput Nucleotide Sequencing; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - genetics; HIV-1 tropism; Humans; Maraviroc - therapeutic use; NGS; Phenotype; Receptors, HIV - classification; Receptors, HIV - genetics; Software; Subtype A; Viral Tropism; Viremia; Subtype A; Coreceptor usage; Genotype; Phenotype; NGS; HIV-1 tropism
• ISSN: 1386-6532; 1873-5967
• DOI: 10.1016/j.jcv.2018.12.007

•Assessment of HIV-1 coreceptor usage with Geno2Pheno[coreceptor] (G2P[c]) algorithm.•Performance of G2P[c] for prediction of tropism with subtype A/CRF02_AG vs. subtype B.•Gold-standard tropism assignment by a phenotypical homebrew single-cycle assay.•Analysis of discrepant genotype-phenotype results by Next Generation Sequencing.
Assessment of human immunodeficiency virus type 1 (HIV-1) coreceptor usage is required prior to treatment with the CCR5 antagonist maraviroc to exclude the presence of CXCR4-using (X4) strains. Genotype-based interpretation systems are mostly designed on subtype B and have been reported to be less accurate for subtype A/CRF02_AG.
To evaluate the performance of the widely used Geno2Pheno[coreceptor] (G2P[c]) algorithm for prediction of coreceptor usage with subtype A/CRF02_AG vs. subtype B.
Co-receptor tropism of 24 subtype A/CRF02_AG and 24 subtype B viruses was measured phenotypically by a homebrew single-cycle assay and genotypically by using G2P[c]. Samples with discrepant genotype-phenotype results were analyzed by next generation sequencing (NGS) and interpreted by the NGS Geno2Pheno algorithm (G2P[454]).
At 10% false positive rate (FPR), the G2P[c]/phenotype discordance rate was 12.5% (n = 3) for subtype A/CRF02_AG and 8.3% (n = 2) for subtype B. Minority X4 species escaping detection by bulk sequencing but documented by NGS explained the two subtype B and possibly one subtype A/CRF02_AG discordant case. The other two subtype A/CRF02_AG miscalled by G2P[c] could be explained by X4 overcalling at borderline FPR and/or by algorithm failure.
Our study did not demonstrate relevantly higher G2P[c] inaccuracy with subtype A/CRF02_AG with respect to subtype B. Genotype/phenotype discordances can be due to different reasons, including but not limited to, algorithm inaccuracy. Very large genotype/phenotype correlation panels are required to detect and explain the reason for any consistent difference in genotypic tropism prediction for subtype A/CRF02_AG vs. subtype B.