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

0393023 - ÚOCHB 2014 RIV US eng J - Journal Article
Weber, Jan - Vazquez, A. C. - Winner, D. - Gibson, R. M. - Rhea, A. M. - Rose, J. D. - Wylie, D. - Henry, K. - Wright, A. - King, K. - Archer, J. - Poveda, E. - Soriano, V. - Robertson, D. L. - Olivo, P. D. - Arts, E. J. - Quinones-Mateu, M. E.
Sensitive Cell-Based Assay for Determination of Human Immunodeficiency Virus Type 1 Coreceptor Tropism.
Journal of Clinical Microbiology. Roč. 51, č. 5 (2013), s. 1517-1527. ISSN 0095-1137. E-ISSN 1098-660X
Grant - others:NIH(US) P30 AI036219
Institutional support: RVO:61388963
Keywords : HIV tropism * phenotypic assay * genotypic prediction * disease progression * CCR5 antagonists * naive patients
Subject RIV: EE - Microbiology, Virology
Impact factor: 4.232, year: 2013

CCR5 antagonists are a powerful new class of antiretroviral drugs that require a companion assay to evaluate the presence of CXCR4-tropic viruses prior to use in human immunodeficiency virus (HIV)-infected individuals. In this study, we have developed, characterized, verified, and prevalidated a novel phenotypic test to determine HIV-1 coreceptor tropism (VERITROP) based on a sensitive cell-to-cell fusion assay. The env-expressing vectors were used in a cell-to-cell fusion assay to determine the presence of R5 and/or non-R5 HIV-1 variants within the viral population. Results were compared with (i) the original version of Trofile, (ii) population sequencing, and (iii) 454 pyrosequencing, with the genotypic data analyzed using several bioinformatics tools, i. e., the 11/24/25 rule, Geno2Pheno, and webPSSM. VERITROP consistently detected minority non-R5 variants from clinical specimens, with an analytical sensitivity of 0.3%, with viral loads of >= 1,000 copies/ml, and from B and non-B subtypes. In a pilot study, a 73.7% (56/76) concordance was observed with the original Trofile assay, with 19 of the 20 discordant results corresponding to non-R5 variants detected using VERITROP and not by the original Trofile assay. The degree of concordance of VERITROP and Trofile with population and deep sequencing results depended on the algorithm used to determine HIV-1 coreceptor tropism. Overall, VERITROP showed better concordance with deep sequencing/Geno2Pheno at a 0.3% detection threshold (67%), whereas Trofile matched better with population sequencing (79%). However, 454 sequencing using Geno2Pheno at a 10% FPR and 0.3% threshold and VERITROP more accurately predicted the success of a maraviroc-based regimen. In conclusion, VERITROP may promote the development of new HIV coreceptor antagonists and aid in the treatment and management of HIV-infected individuals prior to and/or during treatment with this class of drugs.
Permanent Link: http://hdl.handle.net/11104/0221782