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

Autor: Valentina Svicher, Fabio Continenza, Ada Bertoli, Isabella Romeo, Fabiola Di Santo, Enrico Girardi, Nicola Petrosillo, Nicoletta Orchi, Matteo Surdo, Carmela Pinnetti, Carlo Federico Perno, Massimo Andreoni, Giuseppina Liuzzi, Massimo Giuliani, Alessandra Latini, Maria Mercedes Santoro, Valentina Fedele, Claudia Alteri, Antonella d'Arminio Monforte, Anna Artese, Lucia Parrotta, Giosuè Costa, Velia Chiara Di Maio, Andrea Antinori, Francesca Ceccherini-Silberstein, Stefano Alcaro, Stefania Carta, Rita Bellagamba, Caterina Gori
Rok vydání: 2016
Předmět:
Zdroj: Journal of Global Antimicrobial Resistance. 7:1-7
ISSN: 2213-7165
DOI: 10.1016/j.jgar.2016.06.005
Popis: 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±3.5nM; and IC90,FTC, 12.4±7.7 vs. 16.8±9.8nM, respectively). The efficacy of FTC, abrogated by M184V, was partially restored by A98S (IC90,FTC, 5169±5931nM for A98S+M184V vs. 18477±12478nM for M184V 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.
Databáze: OpenAIRE
Externí odkaz: