The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro

Claudia Alteri, M. Surdo, Velia Chiara Di Maio, F. Di Santo, Giosuè Costa, L. Parrotta, Isabella Romeo, Caterina Gori, Maria Mercedes Santoro, Valentina Fedele, Stefania Carta, Fabio Continenza, Carmela Pinnetti, Rita Bellagamba, Giuseppina Liuzzi, Nicoletta Orchi, Alessandra Latini, Ada Bertoli, Enrico Girardi, Stefano AlcaroMassimo Giuliani, Nicola Petrosillo, M. Andreoni, Andrea Antinori, Antonella D. Monforte, F. Ceccherini-Silberstein, Anna Artese, Carlo Federico Perno, Valentina Svicher

Research output: Contribution to journalArticle

Abstract

The impact of baseline HIV-1 reverse transcriptase (RT) polymorphisms on response to first-line modern HAART containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) was evaluated. The impact of each RT polymorphism on virological success (VS) was evaluated in 604 HIV-1 subtype B-infected patients starting TDF + FTC-containing HAART. TDF and FTC antiviral activity was also tested in PBMCs infected by mutagenised HIV. Structural analysis based on docking simulations was performed. A98S was the only mutation significantly correlated with an increased proportion of patients achieving VS at 24 weeks (94.0% vs. 84.3%; P = 0.03). Multivariate regression and Cox model analyses confirmed this result. At concentrations close to the minimal concentration achieved in patient plasma, TDF and FTC exhibited higher potency in the presence of A98S-mutated virus compared with wild-type (IC90,TDF, 8.6 ± 1.1 vs. 19.3 ± 3.5 nM; and IC90,FTC, 12.4 ± 7.7 vs. 16.8 ± 9.8 nM, respectively). The efficacy of FTC, abrogated by M184V, was partially restored by A98S (IC90,FTC, 5169 ± 5931 nM for A98S + M184V vs. 18 477 ± 12 478 nM for M184 V alone). Docking analysis showed the higher potency of TDF and FTC in the presence of A98S-mutated virus was mainly due to higher binding affinity between drugs and mutated RT compared with wild-type. In the presence of FTC, A98S also partially restored the RT binding affinity impaired by M184V alone. A98S polymorphism improves virological response to TDF + FTC-containing HAART. This may help clinicians in the choice of the optimal NRTI backbone aimed at achieving maximal virological inhibition.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalJournal of Global Antimicrobial Resistance
Volume7
DOIs
Publication statusPublished - Dec 1 2016

Fingerprint

Tenofovir
Highly Active Antiretroviral Therapy
RNA-Directed DNA Polymerase
Viruses
Human immunodeficiency virus 1 reverse transcriptase
In Vitro Techniques
Emtricitabine
Proportional Hazards Models
Antiviral Agents
HIV-1

Keywords

  • Docking analysis
  • HAART
  • HIV-1
  • Reverse transcriptase
  • Virological success

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Immunology and Allergy
  • Microbiology (medical)

Cite this

The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro. / Alteri, Claudia; Surdo, M.; Di Maio, Velia Chiara; Di Santo, F.; Costa, Giosuè; Parrotta, L.; Romeo, Isabella; Gori, Caterina; Santoro, Maria Mercedes; Fedele, Valentina; Carta, Stefania; Continenza, Fabio; Pinnetti, Carmela; Bellagamba, Rita; Liuzzi, Giuseppina; Orchi, Nicoletta; Latini, Alessandra; Bertoli, Ada; Girardi, Enrico; Alcaro, Stefano; Giuliani, Massimo; Petrosillo, Nicola; Andreoni, M.; Antinori, Andrea; Monforte, Antonella D.; Ceccherini-Silberstein, F.; Artese, Anna; Perno, Carlo Federico; Svicher, Valentina.

In: Journal of Global Antimicrobial Resistance, Vol. 7, 01.12.2016, p. 1-7.

Research output: Contribution to journalArticle

Alteri, C, Surdo, M, Di Maio, VC, Di Santo, F, Costa, G, Parrotta, L, Romeo, I, Gori, C, Santoro, MM, Fedele, V, Carta, S, Continenza, F, Pinnetti, C, Bellagamba, R, Liuzzi, G, Orchi, N, Latini, A, Bertoli, A, Girardi, E, Alcaro, S, Giuliani, M, Petrosillo, N, Andreoni, M, Antinori, A, Monforte, AD, Ceccherini-Silberstein, F, Artese, A, Perno, CF & Svicher, V 2016, 'The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro', Journal of Global Antimicrobial Resistance, vol. 7, pp. 1-7. https://doi.org/10.1016/j.jgar.2016.06.005
Alteri, Claudia ; Surdo, M. ; Di Maio, Velia Chiara ; Di Santo, F. ; Costa, Giosuè ; Parrotta, L. ; Romeo, Isabella ; Gori, Caterina ; Santoro, Maria Mercedes ; Fedele, Valentina ; Carta, Stefania ; Continenza, Fabio ; Pinnetti, Carmela ; Bellagamba, Rita ; Liuzzi, Giuseppina ; Orchi, Nicoletta ; Latini, Alessandra ; Bertoli, Ada ; Girardi, Enrico ; Alcaro, Stefano ; Giuliani, Massimo ; Petrosillo, Nicola ; Andreoni, M. ; Antinori, Andrea ; Monforte, Antonella D. ; Ceccherini-Silberstein, F. ; Artese, Anna ; Perno, Carlo Federico ; Svicher, Valentina. / The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro. In: Journal of Global Antimicrobial Resistance. 2016 ; Vol. 7. pp. 1-7.
@article{63e48921a14640088656df46d63b388d,
title = "The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro",
abstract = "The impact of baseline HIV-1 reverse transcriptase (RT) polymorphisms on response to first-line modern HAART containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) was evaluated. The impact of each RT polymorphism on virological success (VS) was evaluated in 604 HIV-1 subtype B-infected patients starting TDF + FTC-containing HAART. TDF and FTC antiviral activity was also tested in PBMCs infected by mutagenised HIV. Structural analysis based on docking simulations was performed. A98S was the only mutation significantly correlated with an increased proportion of patients achieving VS at 24 weeks (94.0{\%} vs. 84.3{\%}; P = 0.03). Multivariate regression and Cox model analyses confirmed this result. At concentrations close to the minimal concentration achieved in patient plasma, TDF and FTC exhibited higher potency in the presence of A98S-mutated virus compared with wild-type (IC90,TDF, 8.6 ± 1.1 vs. 19.3 ± 3.5 nM; and IC90,FTC, 12.4 ± 7.7 vs. 16.8 ± 9.8 nM, respectively). The efficacy of FTC, abrogated by M184V, was partially restored by A98S (IC90,FTC, 5169 ± 5931 nM for A98S + M184V vs. 18 477 ± 12 478 nM for M184 V alone). Docking analysis showed the higher potency of TDF and FTC in the presence of A98S-mutated virus was mainly due to higher binding affinity between drugs and mutated RT compared with wild-type. In the presence of FTC, A98S also partially restored the RT binding affinity impaired by M184V alone. A98S polymorphism improves virological response to TDF + FTC-containing HAART. This may help clinicians in the choice of the optimal NRTI backbone aimed at achieving maximal virological inhibition.",
keywords = "Docking analysis, HAART, HIV-1, Reverse transcriptase, Virological success",
author = "Claudia Alteri and M. Surdo and {Di Maio}, {Velia Chiara} and {Di Santo}, F. and Giosu{\`e} Costa and L. Parrotta and Isabella Romeo and Caterina Gori and Santoro, {Maria Mercedes} and Valentina Fedele and Stefania Carta and Fabio Continenza and Carmela Pinnetti and Rita Bellagamba and Giuseppina Liuzzi and Nicoletta Orchi and Alessandra Latini and Ada Bertoli and Enrico Girardi and Stefano Alcaro and Massimo Giuliani and Nicola Petrosillo and M. Andreoni and Andrea Antinori and Monforte, {Antonella D.} and F. Ceccherini-Silberstein and Anna Artese and Perno, {Carlo Federico} and Valentina Svicher",
year = "2016",
month = "12",
day = "1",
doi = "10.1016/j.jgar.2016.06.005",
language = "English",
volume = "7",
pages = "1--7",
journal = "Journal of Global Antimicrobial Resistance",
issn = "2213-7165",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - The HIV-1 reverse transcriptase polymorphism A98S improves the response to tenofovir disoproxil fumarate + emtricitabine-containing HAART both in vivo and in vitro

AU - Alteri, Claudia

AU - Surdo, M.

AU - Di Maio, Velia Chiara

AU - Di Santo, F.

AU - Costa, Giosuè

AU - Parrotta, L.

AU - Romeo, Isabella

AU - Gori, Caterina

AU - Santoro, Maria Mercedes

AU - Fedele, Valentina

AU - Carta, Stefania

AU - Continenza, Fabio

AU - Pinnetti, Carmela

AU - Bellagamba, Rita

AU - Liuzzi, Giuseppina

AU - Orchi, Nicoletta

AU - Latini, Alessandra

AU - Bertoli, Ada

AU - Girardi, Enrico

AU - Alcaro, Stefano

AU - Giuliani, Massimo

AU - Petrosillo, Nicola

AU - Andreoni, M.

AU - Antinori, Andrea

AU - Monforte, Antonella D.

AU - Ceccherini-Silberstein, F.

AU - Artese, Anna

AU - Perno, Carlo Federico

AU - Svicher, Valentina

PY - 2016/12/1

Y1 - 2016/12/1

N2 - The impact of baseline HIV-1 reverse transcriptase (RT) polymorphisms on response to first-line modern HAART containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) was evaluated. The impact of each RT polymorphism on virological success (VS) was evaluated in 604 HIV-1 subtype B-infected patients starting TDF + FTC-containing HAART. TDF and FTC antiviral activity was also tested in PBMCs infected by mutagenised HIV. Structural analysis based on docking simulations was performed. A98S was the only mutation significantly correlated with an increased proportion of patients achieving VS at 24 weeks (94.0% vs. 84.3%; P = 0.03). Multivariate regression and Cox model analyses confirmed this result. At concentrations close to the minimal concentration achieved in patient plasma, TDF and FTC exhibited higher potency in the presence of A98S-mutated virus compared with wild-type (IC90,TDF, 8.6 ± 1.1 vs. 19.3 ± 3.5 nM; and IC90,FTC, 12.4 ± 7.7 vs. 16.8 ± 9.8 nM, respectively). The efficacy of FTC, abrogated by M184V, was partially restored by A98S (IC90,FTC, 5169 ± 5931 nM for A98S + M184V vs. 18 477 ± 12 478 nM for M184 V alone). Docking analysis showed the higher potency of TDF and FTC in the presence of A98S-mutated virus was mainly due to higher binding affinity between drugs and mutated RT compared with wild-type. In the presence of FTC, A98S also partially restored the RT binding affinity impaired by M184V alone. A98S polymorphism improves virological response to TDF + FTC-containing HAART. This may help clinicians in the choice of the optimal NRTI backbone aimed at achieving maximal virological inhibition.

AB - The impact of baseline HIV-1 reverse transcriptase (RT) polymorphisms on response to first-line modern HAART containing tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) was evaluated. The impact of each RT polymorphism on virological success (VS) was evaluated in 604 HIV-1 subtype B-infected patients starting TDF + FTC-containing HAART. TDF and FTC antiviral activity was also tested in PBMCs infected by mutagenised HIV. Structural analysis based on docking simulations was performed. A98S was the only mutation significantly correlated with an increased proportion of patients achieving VS at 24 weeks (94.0% vs. 84.3%; P = 0.03). Multivariate regression and Cox model analyses confirmed this result. At concentrations close to the minimal concentration achieved in patient plasma, TDF and FTC exhibited higher potency in the presence of A98S-mutated virus compared with wild-type (IC90,TDF, 8.6 ± 1.1 vs. 19.3 ± 3.5 nM; and IC90,FTC, 12.4 ± 7.7 vs. 16.8 ± 9.8 nM, respectively). The efficacy of FTC, abrogated by M184V, was partially restored by A98S (IC90,FTC, 5169 ± 5931 nM for A98S + M184V vs. 18 477 ± 12 478 nM for M184 V alone). Docking analysis showed the higher potency of TDF and FTC in the presence of A98S-mutated virus was mainly due to higher binding affinity between drugs and mutated RT compared with wild-type. In the presence of FTC, A98S also partially restored the RT binding affinity impaired by M184V alone. A98S polymorphism improves virological response to TDF + FTC-containing HAART. This may help clinicians in the choice of the optimal NRTI backbone aimed at achieving maximal virological inhibition.

KW - Docking analysis

KW - HAART

KW - HIV-1

KW - Reverse transcriptase

KW - Virological success

UR - http://www.scopus.com/inward/record.url?scp=84979783770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979783770&partnerID=8YFLogxK

U2 - 10.1016/j.jgar.2016.06.005

DO - 10.1016/j.jgar.2016.06.005

M3 - Article

VL - 7

SP - 1

EP - 7

JO - Journal of Global Antimicrobial Resistance

JF - Journal of Global Antimicrobial Resistance

SN - 2213-7165

ER -