Hepatitis C virus variants resistant to macrocyclic NS3-4A inhibitors subvert IFN-β induction by efficient MAVS cleavage.

BACKGROUND & AIMS: The hepatitis C virus (HCV) NS3-4A protease is essential for the HCV life cycle and a prime target of antiviral treatment strategies. Protease inhibitors, however, are limited by emergence of resistance-associated amino acid variants (RAVs). The capacity to cleave and inactivate mitochondrial antiviral-signaling protein (MAVS) in the RIG-I-signaling pathway is a cardinal feature of NS3-4A, by which HCV blocks induction of interferon-(IFN)-β, thereby promoting viral persistence. Here, we aimed to investigate the impact of NS3-4A RAVs on MAVS cleavage. METHODS: The impact of NS3-4A RAVs on MAVS cleavage was assessed using immunoblot analyses, luciferase reporter assays and molecular dynamics simulations to study the underlying molecular principles. IFN-β was quantified in serum from patients with different NS3-4A RAVs. RESULTS: We show that macrocyclic NS3-4A RAVS with substitutions at residue D168 of the protease result in an increased capacity of NS3-4A to cleave MAVS and suppress IFN-β induction compared with a comprehensive panel of RAVs and wild type HCV. Mechanistically, we show the reconstitution of a tight network of electrostatic interactions between protease and the peptide substrate that allows much stronger binding of MAVS to D168 RAVs than to the wild-type protease. Accordingly, we could show IFN-β serum levels to be lower in patients with treatment failure due to the selection of D168 variants compared to R155 RAVs. CONCLUSIONS: Our data constitutes a proof of concept that the selection of RAVs against specific classes of direct antivirals can lead to the predominance of viral variants with possibly adverse pathogenic characteristics.

Geografisk Charta öfver Hattula socken belägen i Tavastehus län - [Yleisnäkymä - Overview]

[S.l.] [1800-1820?]

[The World] : Ant. Lafreri exc. - [Yleiskuva - Overview]

Roma : Antonio Lafreri 1572

Karlberg

Järvimaisema Aulangolta. Vastarannalla puiden keskellä Karlbergin kartano ja linnanrauniot.

Torneå

Helsingfors : A.W. Gröndahl & A.C. Öhman 1845 : Dresden, Adler u. Dietze

Hans Kejserliga Majestäts Nådiga Försäkran till samtelige Finlands Inbyggare; Gifwen Borgå, den 15/27 Martii 1809 - [Titelsidan]

Åbo 1809, Frenckell

Luettelo lainakirjaston kirjoista Wesilahdella, wuosina 1895- - 1

Tampere 1895

Nissanim - 1-25

Sisällys/Contents: 1. ¿Andersen: ham-Mal¿ak. Targum: ¿Abi¿asap. 2. ¿Andersen: Be-¿aharit-jam. 3. ¿Andersen: Tippat ham-majim. & ha-Hol. 4-5. Andersen: Perah qatan. 6. H. Lewe: Perah nipla¿. & Qeren hash-shemesh. 7-8. Maqs Nordo: Siah hash-shoshannim. Targum: Sh.L. Gordon. 9. P. ¿Awwirpuk: ¿Ateret haz-zahab. 10. ¿A. Terje: he-Halil han-nipla¿. Targum: P. ¿Awwirpuk. 11-15. Ma¿asijjot liladim. Targum: Shelomo Berman. 16. Mika Josep Berditshevsqi: Ma¿asijjot we-¿aggadot. 17-18. Herodot: Hekal ra¿meses. ¿al jede: ¿A-S. 19. J.V. Levner: hab-Kotel ham-ma¿arabi. 20. ¿A.L. Ja¿aqubovis: ¿Abraham hak-Kaspi. 21-22. Sha¿ul Tshernihovsqi: Shirim. 23-25. Jishaq J. Qassenelson. Shirim.

Paysages du Nord: Russes, Lapons, Suédois

Paris [1856]

La Lapponia Russa coi Governi di Olonechoi, Carelia, Bielozero, ed Ingria Nella Russia Europea di nuova projezione - [Yleisnäkymä - Overview]

Venezia : Presso Antonio Zatta 1782

Tampereen Puuvillateollisuus Oy., (Lapinniemi)

Kuvalla nimeke myös ruotsiksi, saksaksi ja englanniksi.