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Deep-Sequencing Analysis of the Dynamics of HIV-1 Quasiespecies in Naive Patients during a Short Exposure to Maraviroc.

Deep-Sequencing Analysis of the Dynamics of HIV-1 Quasiespecies in Naive Patients during a Short Exposure to Maraviroc.
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Cascajero A, Rastrojo A, Díez-Fuertes F, Hernández-Novoa B, Aguado B, Moreno S, Alcami J, Pérez-Olmeda M,


Cascajero A, Rastrojo A, Díez-Fuertes F, Hernández-Novoa B, Aguado B, Moreno S, Alcami J, Pérez-Olmeda M, (click to view)

Cascajero A, Rastrojo A, Díez-Fuertes F, Hernández-Novoa B, Aguado B, Moreno S, Alcami J, Pérez-Olmeda M,

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Journal of virology 2018 03 21() pii 10.1128/JVI.00390-18

Abstract

In this study we have characterized quasispecies dynamics and the evolution of viral tropism in naive HIV-1-infected patients treated with a short-course of maraviroc monotherapy (NCT01060618) independently of their tropism. We randomly selected 20 patients displaying different basal tropism -10 R5 and 10 DMX4- at recruitment as determined by phenotypic tests (Trofile). Evolution of viral quasiespecies at the end of treatment was determined by ultra-deep sequencing of the V3 region using a 454 Life Sciences Platform and geno2pheno (g2p) algorithm for viral tropism prediction. False Positive Rate (FPR) that defines the probability of classifying an R5-virus falsely as X4 was set at 10% .Viral load (VL) X4 was calculated from sequences with FPR < 3.75.Virological response as defined as >1 logreduction in VL was detected in 70% of patients independently of their basal tropism. Viral tropism remained stable and non-significant differences in FPR values before and after treatment was found for the majority of patients in both tropism groups. Only 3 patients (1 R5 and 2 DM/X4) showed an increased (>1log) VL-X4 and one patient with DM/X4 tropism displayed a significant reduction in FPR values at the end of treatment. Fast changes in the composition of viral populations were observed in all patients after 10-day of MVC monotherapy treatment and a complete replacement of viral quasiespecies was found in 3/10 patients carrying R5-using viruses and 4/10 DM/X4-using viruses.Initiation of treatment with maraviroc requires previous determination of tropism by genotypic or phenotypic methods because the risk of treatment failure and selection of DM/X4-tropic variants. In this study we confirm previous work showing that virologic response to maraviroc is independent of basal tropism. By deep-sequencing analysis we determined that fast changes in viral populations were due to the emergence of minority variants in some patients whereas in others generation of new strains were detected. The risk of DM/X4 selection was very low as FPR values remained stable and only one patient showed a detrimental switch to DM/X4 variants. Our data show that some DM/X4 viruses are sensitive to maraviroc treatment probably because only a low proportion of DM/X4 uses preferentially the X4 receptor and contain authentically maraviroc-resistant viruses that are not accurately detected by current assays.

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