Novel HCV Inhibitors

The UseNovel of Antivirals HCV toInhibitors Rapidly Contain Outbreaks of the Classical Swine Fever Virus

Johan Neyts Rega Institute, KULeuven, Leuven Belgium

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Selective Inhibitors of HCV Replication that Target NS Proteins

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS2 cysteine protease

NS2/3 cleavage is essential for replication and assembly

N N

C C

Active Site 1 Active Site 2

Lorenz et al. Nature (2006) 442: 831-5

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The HCV NS3 serine protease

N-terminal domain : a serine protease in the presence of the NS4A cofactor protein

C-terminal domain : RNA helicase

De Francesco et al. 2001 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS3 protease product based inhibitors

carboxy-terminal hexapeptide products as an active-site affinity anchor

BILN-2061

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Proof of concept with BILN-2061 (Ciluprevir)

Lamarre et al., Nature. (2003) 426:186-9.

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Telaprevir monotherapy

placebo

1250 mg q12h

450 mg q8h

750 mg q8h

Reesink et al., Hepatology (2005) 42 : 234A Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The Major VX-950 and BILN2061 Resistance Mutations Do Not Cause Cross-resistance

ITMN-191 Ciluprevir

Lin, C. et al. J. Biol. Chem. (2004) 279:17508-17514

Telaprevir Boceprevir TMC435350

Others : GS9256 - BI201335 - BMS-650032 - RG7227 - IDX320 - ABT-450

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Resistance mutations selected by protease inhibitors

T54T-V R155Q A156S/T D168V/A

Telaprevir (VX950) XX

Boceprevir X X

TMC435350 XXX

ITMN-191 X X

Ciluprevir (BILN- XX X 2061)

Adapted from Sheldon et al., (2007) Expert Opinion Anti-Infectives Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS3 Helicase as an Antiviral Target

Dr. A. Brancale (Cardiff)

Kim et al (1998) Structure. 15:89-100 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS4A/NS3 inhibitors

Mutations located where extensive No cross resistance with (other) interactions with NS4A exist. NS3 and with NS5B inhibitors Yang et al., (2008), Antimicrob. Agents & Chemother.

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS4B as an Antiviral Target

NS4B : difficult to express membrane protein that is believed to interact with viral RNA

Binding assay of 3’ terminal –ssRNA (labelled) to <<< quantity of NS4B protein library screen

Clemizole

Einav et al., Nat. Biotech.2008 NS4B Further reading : Gouttenoire, Penin & Moradpour, Rev. Med. Virol (2010)

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A as an Antiviral Target

BMS-790052

Membrane-associated phosphoprotein involved in replication and virus production. No enzymatic activity associated

ER membrane Membrane Cytosol anchor AA 1 to 30 : membrane anchor,Resistance directing NS5Amutations to the likely ER located at Domain I (without α- Domain 1 the membrane interface helix) crystallizes as a AA 5 to 25 : amphipathic α-helix with a lipid colinear homodimer bilayer-associated hydrophobic face and a (Tellinghuize et al., solvent-exposed polar face Love et al.). Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052)

BMS-790052

Not cross resistant with other HCV inhibitors 31, 30, 28, 23 93 Mutations in N-terminus of domain 1.

If transitioning between dimer configurations is important for HCV replication BMS-790052 may possibly influence this transition.

May possibly prevent formation of a multiprotein complex on ER membrane.

Resistance mutations likely located atBlocks the the hyperphosphorylation of NS5A Gao et al., (2010) Nature membrane interface (essential role in the viral life cycle).

Causes redistribution of NS5A

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052)

Scheel et al., Hepatology, 2010 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus NS5A inhibitor (BMS-790052)

Mean change in HCV RNA following a single oral dose Phase II studies (phase I study) combining BMS- 790052 with the NS3 protease inhibitor BMS-650032 are ongoing.

This combination (alone or with PEGIFN and RBV) results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders Gao et al., (2010) Nature

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus The NS5B RNA dependent RNA polymerase

Bresanelli & Rey

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Nucleoside inhibitors

MK-0608

R7128 : di-isobutyl ester prodrug of PSI-6130 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzimidazole/indoles

Intramolecular contacts between the thumb and the finger domain may force the enzyme into an 1 ‘open’, inactive conformation

O COOH H N HO N O N

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Thiophene carboxylic acid / Pyranoindole / Dihydropyranone

VCH-916, PF-868554/Filibuvir,

Met423 Leu419

O S OH O

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzothiadiazine/Acylpyrrolidines

ABT-333 ANA598,

O O O S O O N N

N O N

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Non- Nucleoside inhibitors Benzofuran CH O 3 N H O F S O O N

C316F/Y C445F

4 3

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Combinations of Non Nuc NS5B Inhibitors Delay or Prevent Resistance Development

Delang et al., 2011 J. Hepatol, in press

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Double and triple resistant variants

Delang et al. , J. Hepatol, in press (2011)

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Discovery of the imidazopyridine GS-9190 (Tegobuvir)

BPIP compound 1 compound 2 compound 3

F F F F N N N N

N N N N N N N N

Br CF Br Br 3

HCV BVDV HCV BVDV HCV BVDV HCV BVDV

EC50 >50 0.07 ± 0.02 EC50 3.0 ± 1.6 0.12 ± 0.01 EC50 0.6 ± 0.1 0.24 ± 0.12 EC50 0.2 ± 0.1 0.25 ± 0.09

CC50 80 ± 11 83 ± 20 CC50 136 ± 42 >33 CC50 >55 >100 CC50 >119 >100

compound 4 GS-327073 F F F F N N GS-9190 (Tegobuvir) N N N N HCV : 1nM / BVDV > 50µM

O ~ 2000 cpds N

CF 3

Cl HCV BVDV HCV BVDV

9 EC50 0.1 ± 0.01 0.72 ± 0.19 EC50 0.004 ± 0.002 1.4 ± 0.96 CC50 108 >100 CC50 ≥ 19 >100 ~ 1700 Vliegen et al. (2009), J. Hepatol. molecules Purstinger et al., (2006 b, c) Bioorg. Med. Chem. Letters

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus GS-9190 (Tegobuvir) targets the HCV RdRp with a GS-9190 (Tegobuvir)unique mechanism targets the HCV RdRp

C445F - Y448H - Y452H - C316F/Y

Beta hairpin loop involved in primer independent initiation of RNA replication.

Partially cross resistant with benzofurans

Compound does not inhibit the purified RdRp.

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Tegobuvir Phase IIa study (196-0112)

Zeuzem et al., 61st AASLD (The Liver Meeting, Nov. 2010) Boston.

Treatment-naive adults with chronic HCV genotype 1 (28-days treatment course)

GS-9190 (40 mg twice daily) Median maximal decline from baseline GS-9256 (75 mg twice daily) HCV RNA of 4.1 log10 IU/mL

GS-9190 (40 mg twice daily) Median maximal decline from baseline in GS-9256 (75 mg twice daily) HCV RNA of 5.1 log10 IU/mL. RBV (500 - 600 mg twice daily)

GS-9190 (40 mg twice daily) 14/14 patients : HCV RNA < 25 IU/mL) at day 28. Median maximal decline from GS-9256 (75 mg twice daily) baseline in HCV RNA 5.7 log10 IU/mL RBV (500 - 600 mg twice daily) 13/14 patients : undetectable viral levels Peg-IFN (180 µg, inj. once/week) (HCV RNA < 10 IU/mL) at day 28. No virologic breakthroughs

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Tegobuvir + Telaprevir

3 day antiviral combination assay Clearance rebound assay

No compound 5 x EC50 G418 pressure 100 80 120 60 100 40 80 20 60 0 40 -20 expected -40 20 -60 0.00015 0 0.0014

-80 Percentage of UTC (%) 0.012 C0 C1 C2 C3 R1 R2 R3 R4 % inhibition above or below % inhibition above -100 GS-9190 0.11 (µM)

1.0 1.0 0.33 0.11 VX-950 0.037 0.012 0.0041 VX-950 (µM) 0.0014 GS-073 + VX-950 0.00046 GS-073

Vliegen et al., J. Hepatol. 2009 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Triple combinations

Clearence/rebound GS9190-9xEC50 Clearence/rebound GS9190-25xEC50 Clearence/rebound GS9190-125xEC50

R4 R4 R4 ►►100 R3 100 R3 R3 100 C3R1 DEATH rebound rebound rebound % replicon % replicon 75 % replicon 75 R2 75 R2 passage R2 passage passage RNA as RNA as RNA as 50 number 50 number 50 number compared to R1 compared to R1 compared to R1 control 25 control 25 control 25 R0 R0 R0 0 0 0 123456 123456 123456 clearence passage number clearence passage number clearence passage number

Clearence/rebound 2'CMC-9xEC50 Clearence/rebound 2'CMC-25xEC50

Triple Combi R4 R4 100 R3 ► Clearence/rebound GS-9190-9x + 2'CMC-9x R3 rebound 100 % replicon 75 rebound + VX-950-9x R2 passage % replicon 75 RNA as R2 pa ssa ge 50 number RNA as compared to R1 50 number compared to R1 control 25 R0 control 25 R0 0 0 123456 123456 clearence passage number clearence passage number R4 R3 100 rebound Clearence/rebound VX-950-9xEC50 Clearence/rebound VX-950-25xEC50 % replicon C2R1 DEATH 75 R2 pa ssa ge RNA as 50 number compared to R1 25 control R0 0 123456 clearence passage number

R4 R4

100 R3 100 R3 rebound rebound % replicon ► 75 R2 passage % replicon 75 R2 passage RNA as RNA as 50 number 50 number compared to R1 compared to R1 control 25 25 R0 control R0 0 0 123456 123456 clearence passage number clearence passage number

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Combinations

Some combinations that are in phase II

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Alisporivir (Debio-025) a cyclophylin binding HCV inhibitor

Cyclophilin binding domain DEBIO-025

HO O

N N N O N N H O O O O N H O H O N O N N H N N O O Calcineurin binding domain

Name Pos3 N4 Pos4 CsA H Me Leu Watashi et al., BBRC (2003) DEBIO-025 Ala Et Val

Paeshuyse et al., Hepatology (2006) Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Alisporivir is not cross-resistant with other HCV No cross-resistance with other DAA inhibitors inhibitors

Alisporivir CsAres 2CMCres BILN VX-950res drug WT R1479res res 2061res

Alisp. 0.04 ± 0.03 ≥1.95 0.23 ± 0.17 0.11 ± 0.27 0.12 ± 0.01 0.1 ± 0.003 0.09 ± 0.01

CsA 0.29 ± 0.05 4.55 ± 3.98 3.82 ±1.00 0.21 ± 0.04 0.26 ± 0.05 0.17 ± 0.06 /

2CMC 0.41 ± 0.16 0.41 ± 0.53 0.41 ± 0.40 >30.15 3.38 ± 1.07 0.29 ± 0.18 1.02 ± 0.70

R1479 2.95 ± 0.88 2.76 ± 0.89 1.98 ± 0.50 1.16 ± 0.43 28.63 ± 8.68 2.16 ± 0.27 /

BILN 0.02 ± 0.01 <0.004 0.004 0.04 ± 0.03 0.02 ± 0.01 1.25 ± 0.47 0.79 ± 0.08 2061

VX-950 0.58 ± 0.10 0.36 ± 0.04 0.49 ± 0.32 1.01 ± 0.32 0.69 ± 0.15 0.31 ± 0.05 13.97 ± 1.4

EC50-values in µM Coelmont L. et al. AAC 2009; 53: 967-976.

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Alisporivir effciently clears HCV replicons from the host cell

120 clearance rebound 100

60 % UTC

0 123456789 passage number

CsA 0.5 µg/ml (0.42 µM) D-025 0.5 µg/ml (0.41 µM) VX-950 5 µg/ml (7.06 µM) IFN 100IU/ml RBV 30 µg/ml (122.85 µM)

Coelmont L. et al. AAC 2009; 53: 967-976. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Alisporivir combination with Telaprevir.

100.00 100.00

90.00 90.00 80.00 80.00 70.00 70.00 60.00 60.00 % UTC 50.00 50.00

40.00 % UTC 40.00 30.00 30.00 20.00 20.00 10.00 10.00 0.00 R2 0.00 R2 1 R1 1 R1 2 3 rebound 2 rebound 4 P 3 P 5 4 5 6 6 passage number 7 passage number 7

VX-950 (7 µM) Debio 025 (0.10 µM)

80.000

70.000

60.000

50.000

C 40.000

% UT 30.000

20.000

10.000

0.000 R2 R1 1 2 rebound 3 P 4 5 Coelmont L. et al. AAC 2009; 53: 6 passage number 7 967-976. Debio 025 (0.10 µM) + VX-950 (7 µM) Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus TheCombinations combination of Alisporivir containing with HCV protease Alisporivir or polymerase prevent inhibitors resistanceprevents development the development against of drug escape other mutants inhibitors. Protease inhibitors

NucIeoside and non-nucleoside polymerase inhibitor

Coelmont L. et al. AAC 2009; 53: 967-976. Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Clinical efficacy of Alisporivir

Patel and Heathcote, Gut, 2010

Flisiak et al., Hepatology (2009)

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus SelectingSelecting Alisporivir Alisporivir resresistantreplicons replicons (GT1b)

Resistance selection is a long process: • Alisporivirres: ± 20 weeks high genetic barrier to resistance •CsAres: ± 23 weeks

120 120

100 100

80 WT80

DEB025 res 60 60 CsA res 40 40

20 20 HCV replicon RNA (% untreated) HCV replicon RNA HCV replicon RNA (% untreated) HCV replicon 0 0 0.01 0.1 1 10 0.01 0.1 1 10 DEB025 (µM) CsA (µM)

Coelmont et al., PLoS ONE, 2011 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus E320DD320E contributescontributes most most to observedto the resistance resistance

NS3 : A241P

NS5A : R262Q -D318W - P - E320D 120 120

100 100

80 80

60 60

40 40

20 20 HCV replicon RNA (% untreated) HCV replicon RNA (% untreated) (% RNA untreated) HCV replicon 0 0 0.01 0.10 1.00 0.01 0.10 1.00 10.00 DEB025 (µM) CsA (µM)

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus PrevalencePrevalence ofof theD320E variants in euHCV in euHCVdatabase database

NS3 NS5A A241P R262Q R318W D320E

Subtype # in EuHCVdb WT2 Variant1 WT2 Variant1 WT2 Variant1 WT2 Variant1 1a 224 A (94%) P (0%) R (96%) Q (0%) R (100%) W (0%) D (100%) E (0%) 1b 350 A (97%) P (0%) R (97%) Q (0.8%) R (98%) W (0%) D (99%) E (0.3%) 2a 19 A (100%) P (0%) del3 (85%) Q (0%) R (100%) W (0%) D (95%) E (5%) 2b 25 A (100%) P (0%) del3 (100%) Q (0%) R (92%) W (0%) D (96%) E (4%) 3 28 S (89%) P (0%) R (100%) Q (0%) R (100%) W (0%) D (100%) E (0%) 4 39 A (77%) P (0%) del3 (88%), R(12%) Q (0%) R (87%) W (0%) D (82%) E (5%)

1Variant identified in the Alisporivirres replicon 2WT AA for that genotype (AA with the highest prevalence) 3del=deletion

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Role of NS5A or NS5B in resistance NS5A or NS5B - swapping

Resistant HCV subgenomic replicon

HCV EMCV neo NS4 5’UTR NS3 NS5A NS5B 3’UTR AB IRES IRES

NS5A NS5B WT HCV subgenomic replicon

HCV EMCV NS4 Luc 5’UTR NS3 NS5ANS5A NS5BNS5B 3’UTR A B IRES IRES

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Swapping of NS5A results in transfer of resistance NS5A - swapping results in transfer of resistance

120 120 100 swap-NS5A-WT100

80 swap-NS5B-WT80

60 swap-NS5A-D025res 60

swap-NS5B-D025res 40 40 original vector 20 20 HCV replicon RNA (% untreated) 0 untreated) RNA (% HCV replicon 0 0.01 0.10 1.00 0.10 1.00 10.00 DEB025 (µM) CsA (µM)

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Debio-025 differs from BMS-790052 NS5A - swapping results in transfer of resistance

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus AlisporivirAlisporivirresresRNARNA isis lessless dependentdependent onon CypACypA forfor replicationreplication

Control cells CypA KD cells

400 140 350 120 300 100 250 CTRL-GND80 200 CTRL-WT 60 150 CTRL-D025res fold 4h-value 100 fold 4h-value 40

50 20

0 0 24h 48h 72h 96h 24h 48h 72h 96h hour post transfection hours post transfection

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Mutations in Alisporivirres NS5A do not preserve the integrity of the interaction NS5A - CypA

NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B. A

µM µM DEB025 DEB025

µM µM CsA CsA

Coelmont et al., PLoS ONE, 2011 Hanoulle et al., J Biol Chem (2009) 284:13589-13601 Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus MutationsMutations in in Alisporivir DEB025resresNS5ANS5A do do not not preserve preserve thethe integrityintegrity ofof thethe interactioninteraction NS5ANS5A -- CypA CypA

µM DEB025

µM CsA

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Shift in cis - trans balance between WT and D320E peptide

308-KFPRAMPIWARPDYNPPLLE-327 308-KFPRAMPIWARPEYNPPLLE-327

trans ↔ cis 75.9% 24.1%

trans ↔ cis 29.6% 70.4%

Coelmont et al., PLoS ONE, 2011

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Working hypothesis MOA CypA inhibitors Hypothesis

CypA HCV replication Normal situation: NS5A

trans to cis isomerization

CypA D025 HCV replication Alisporivir inhibition: NS5A trans ↔ cis

CypA D025 HCV replication Alisporivir resistance: DEB025res NS5A trans ↔ cis Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus OverallConclusions Conclusion

Current therapy is associated with serious side-effects and a large percentage of patients is not cured.

There are a number of excellent targets in the replication cycle of HCV for inhibition of viral replication.

In general drug resistant variants develop rapidly against NS3 protease inhibitors, NS5A inhibitors and NS5B non nucleoside polymerase inhibitors

Drug resistance does not readily develop against NS5B polymerase inhibitors and cyclophylin binding inhibitors.

Combination of three (or possible four) different potent and well tolerated compounds with a non-overlapping resistance profile will likely be the future therapy. This therapy should allow to cure a large percentage of chronically infected patients.

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus Acknowledgement

Rega Institute Univ. Innsbruck Scripps, La Jolla Neyts-lab G. Puerstinger and team P. Gallay L Coelmont U Chatterji M Bobardt J. Paeshuyse Gilead Sciences, CA P Lim K. Geerts Steve Bondy I. Vliegen Weidong Zhong L. Delang Bill Lee and team Pasteur, Lille, France G Lippens A. Vandamme-lab X Hanoulle L. Kerremans Debiopharm J. Snoeck G Vuagniaux R Crabbé JM Dumont Univ. Heidelberg R Bartenschlager C Berger

Presented at the 9th Eu. Workshop on HIV & Hepatitis – 25 – 27 March 2011, Paphos, Cyprus