06.05.2017| Rolf Kaiser HBV 3TC, ADF, TDF, replication- ETV (LdT) - - PowerPoint PPT Presentation

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06.05.2017| Rolf Kaiser HBV 3TC, ADF, TDF, replication- ETV (LdT) - - PowerPoint PPT Presentation

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06.05.2017| Rolf Kaiser HBV 3TC, ADF, TDF, replication- ETV (LdT) cycle and antiviral targets 06.05.2017| Rolf Kaiser Gerlich and Kann in Topley & Wilson 0.25 Product 1 (base 377 to 864) For: 5 GGATGTGTCTGCGGCGTTT3 Rev: 5

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Gerlich and Kann in Topley & Wilson

HBV

replication- cycle and antiviral targets

3TC, ADF, TDF, ETV (LdT)

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N236T 0.25 0.87

Product 1 (base 377 to 864) For: 5’GGATGTGTCTGCGGCGTTT3’ Rev: 5’ACCCCATCTTTTTGTTTTGTTAGG3’ Product 2 (base 252 to 819) For: 5’AGACTCGTGGTGGACTTCTCT3’ Rev: 5’CAAAAGAAAATTGGTAACAGCGGTA3’

Allen et al., 1998

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Angus, Gastroenterology 2003; Delaney ,J Virol 2003; Allen, Hepatology 1998; Colonno, Hepatology 2004

Terminal Protein

L180M+ M204V+

TDF A181V? 198? N236T?

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HBV Genotypes

Schaefer, J Viral Hep 2005

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HBV-Genotype distribution Düsseldorf

47

40 7 3,5 2

Erhardt, Gut , 2005 Jul;54(7):1009-13.

A E B C D G N = 165 [ % ]

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D E A G B

Köln data

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HIV-GRADE Output

  • M. Obermeier

Medizinisches Labor Berg

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HIV-GRADE Output

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geno2pheno[hbv] How to find the Tool: http://www.genafor.org

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geno2pheno[hbv] – Sequence Information

(Sub)Genotype Completeness and Similarity Mutations Escape Mutations

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HBV HBsAg Major hydrophilic loop Mutationen reported with escape

Jens Verheyen, Maria Fraune HBV-Hülle

  • 163

Y Q G M L P L P T C T T G S T G T P K T S I V T A C P Q P C G N M S F C C P P G T C K D C N T T F K Y P S I W L I C S W A A D L

98-

S

G145R

105L 109R/V/H/I *110M/R/H/I/V *114R 117T 118K/R/S/P 119R 120A/E/LP/Q/S/T/R 121S/Y 123A/N 124R/Y *126N/S/V/I/T *127R/S/T 128V 129H/K/P/R 130D/R *131D/I/S 132A/P 133I/L/T/V *134H/N/R/S/V 137R/S/W/Y 139S 140S 141E/I/R 142L/R/S *143L/P 144A/E/G 145A/K/L/R 146D/S 147S/T *Positionen an denen genotyp-spezifische Polymorphismen vorkommen

Prevalence: G145R: 0,4% Schaefer et al., 2004 D144A: 0,7% D144G: 0,4% M133I: 1,8% C124R: 0,4% C124Y: 0,7% T123N: 0,4% ........ _____________ Carman, et al. 1990 Oon et al. 1994

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Assay A Assay B Assay C Assay D Assay E wt-genotype D 100,0% 100,0% 100,0% 100,0% 100,0% P120T 50,0% 7,0% 100,0% 120,0% 140,0% C121Y 3,0% < 1% 5,0% 50,0% 26,0% R122I 24,0% 43,0% 92,0% 120,0% 120,0% T123N 2,7% < 1% 2,0% 110,0% 30,0% C124R 3,1% < 1% 7,0% 40,0% 17,0% T125M 76,0% 83,0% 120,0% 110,0% 130,0% T126I 74,0% 70,0% 120,0% 100,0% 120,0% T126V 64,0% 80,0% 100,0% 110,0% 110,0% G130D 100,0% 56,0% 110,0% 100,0% 110,0% P142S 58,8% < 1% 110,0% 110,0% 150,0% G145R 110,0% < 1% 86,0% 110,0% 110,0%

Axsym Abbott Centaur Siemens Architect Abbott BEP III Siemens Vidas bioMerieux

Recombinant Escape Mutants

Jens Verheyen, Maria Fraune

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geno2pheno[hbv] – PDF Output Sequence Information Drug Resistance Place your own comments For Mailing and Archiving

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I nstitute of Virology, University of Cologne

Rolf Kaiser Elena Knops Veronica Di Cristanziano Maria Neumann-Fraune Eugen Schülter Claudia Müller Dörte Hammerschmidt Ramona Gilles Saleta Sierra-Aragon Eva Heger Baki Akgül Herbert Pfister

Thanks to our group

MASTER –HIV/HEP (RKI, Resina)

Norbert Bannert, Barbara Bartmeyer, Osama Hamouda, Klaus Jansen, Claudia Kücherer, Andrea Hauser; Robert Koch Institut (RKI), Berlin Mark Oette, Dept. Gastroenterologie, Krankenhaus der Augustinerinnen, Cologne Nazifa Quirishi, Katja Römer, Praxis Gotenring, Cologne Stephan Scholten, Praxis Hohenstaufenring, Cologne Stefan Esser, Dermatology, University Clinics Essen Martin Obermeier, Hauke Walter, Thomas Berg, mib, Berlin Patrick Braun, Heribert Knechten, PZB Aachen 18

University of Düsseldorf

Hepatology & I nfectiology

Björn Jensen, Ulrike Haars, Falk Hüttig Verena Keitel, Dieter Häussinger

I nstitute of Virology

Nadine Lübke, Andreas Walker, Jörg Timm

EURESI ST

Francesca Incardona, Informa, Rome Maurizio Zazzi, Andrea De Luca, Uni Siena Anders Sönnerborg, Karolinska, Stockholm Thomas Lengauer, MPI Saarbrücken Rolf Kaiser, Uni Koeln

Institute for Immunogenetics, Kaiserslautern

Martin Däumer, Alex Thielen

MPI for Informatics, Saarbrücken Thomas Lengauer, Nico Pfeifer, Matthias Döring, Alejandro Pironti, Prabhav Kalaghatgi , Funding by MASTER-HIV/HEP –BMG / DZIF-TTU-Hepatitis BMBF

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Geno2pheno[HBV] analyses the Polymerase (RT), Pre Core, sAntigen region of the HBV-genome. Geno2pheno[HBV] predicts drug resistance of 3TC, ETV, TDF Geno2pheno[HBV] analyses the HBV genotype Geno2pheno[HBV] analyses the HBV escape mutants The escape mutations dataset comprises 67 mutations at 28 distinct amino acid positions. geno2pheno [hbv] is capable of detecting cases of dual infection with strains of distinct genotypes. Interpretation is synchronised with HIV-GRADE[HBV] Geno2pheno[HBV] will be prepared to analyse drug resistnace to the new drugs

Summary

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