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±3.5nM; 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.
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Surdo
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Velia Chiara
authors.initials: VC
authors.lastname: Di Maio
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Di Santo
authors.affiliation: University 'Magna Graecia' of Catanzaro, Germaneto, CZ, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.affiliation: University 'Magna Graecia' of Catanzaro, Germaneto, CZ, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Parrotta
authors.affiliation: University 'Magna Graecia' of Catanzaro, Germaneto, CZ, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Romeo
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Gori
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Santoro
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fedele
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Carta
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Continenza
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Pinnetti
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Bellagamba
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Liuzzi
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Orchi
authors.affiliation: San Gallicano Hospital, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Latini
authors.affiliation: University of Rome Tor Vergata, Rome, Italy; University Hospital of Rome Tor Vergata, Rome, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Girardi
authors.affiliation: University 'Magna Graecia' of Catanzaro, Germaneto, CZ, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: San Gallicano Hospital, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Giuliani
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Petrosillo
authors.affiliation: University of Rome Tor Vergata, Rome, Italy; University Hospital of Rome Tor Vergata, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Andreoni
authors.affiliation: INMI 'L. Spallanzani', Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.affiliation: University of Milan, Milan, Italy.
authors.forename: Antonella d'Arminio
authors.initials: AD
authors.lastname: Monforte
authors.affiliation: University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.affiliation: University 'Magna Graecia' of Catanzaro, Germaneto, CZ, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.affiliation: University of Rome Tor Vergata, Rome, Italy; INMI 'L. Spallanzani', Rome, Italy; University Hospital of Rome Tor Vergata, Rome, Italy. Electronic address: cf.perno@uniroma2.it.
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.affiliation: University of Rome Tor Vergata, Rome, Italy. Electronic address: valentina.svicher@uniroma2.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D000068679:Emtricitabine / Q000494:pharmacology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000068698:Tenofovir / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine
keywords: Docking analysis; HAART; HIV-1; Reverse transcriptase; Virological success