University of Cologne Institute of Virology Prevalence of therapy-associated HIV gag CS mutations Jens Verheyen Institut für Virologie Uniklinik Köln Arevir 2009
HIV replication and drugs University of Cologne Institute of Virology Viruseintritt in die Zelle: Fusions-Inhibitor Corezeptor-Blocker Maturation: Protease-Inhibitoren Reverse Transkription: NRTIs, NNRTIs Nukleosidische und Nichtnukleosidische Reverse Transkriptase Inhibitoren Integration proviraler DNA: Integrase-Inhibitoren Arevir 2009
Protease - Substrat - Medikamente University of Cologne Institute of Virology gag-pol gag Viral protease Precursor proteins Protease-Inhibitor Arevir 2009
HIV gag CS mutations University of Cologne Institute of Virology Therapy-associated HIV gag CS mutations CS p17/p24 p24/p2 p2/p7 p7/p1 p1/p6-gag HxB2 VSQNY/PIVQN KARVL/AEAMS SATIM/MQRGN ERQAN/FLGKI RPGNF/LQSRP Mut. I F C P V ERV F TSL I V A H I Y Arevir 2009
Prevalence of HIV gag CS mutations in PI resistant HIV isolates University of Cologne Institute of Virology 100 93,8 87,5 86,9 80 Percent of CS 63,3 positive HIV 60 40,0 40 25,8 20 13,5 Major- PR mutations: 0 24I, 32I, 46I/L, 1 major PR 2 major PR 3 major PR 4 major PR 5 major PR Resistance Resistance with prim. 50V/L, without prim. 54V/L/M/S/T/A, 82A/F/T/S, 84V, 90M TN-HIV TE-HIV Arevir 2009
Correlation between HIV gag CS and PR mutations University of Cologne Institute of Virology all TE- A431V K436R I437V L449F L449V L449P P453A P453L * viruses 225 60 21 35 17 12 10 6 46 n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) 431V: L24I 23 10,1% 14** 23,3% 1 4,8% 3 8,6% 3 17,6% 1 8,3% 0 0,0% 0 0,0% 2 4,3% 24I - 46I - 46L - D30N 18 7,9% 0** 0,0% 2 9,5% 1 2,9% 4* 23,5% 0 0,0% 0 0,0% 0 0,0% 7 15,2% 54V - 82A (30N) V32I 21 9,3% 2 3,3% 4 19,0% 1 2,9% 2 11,8% 1 8,3% 0 0,0% 1 16,7% 1 2,2% L33F 42 18,7% 12 20,0% 6 28,6% 8 22,9% 5 29,4% 2 16,7% 1 10,0% 3 50,0% 7 15,2% 449F: M46I 72 31,7% 27* 45,0% 6 28,6% 13 37,1% 7 41,2% 3 25,0% 2 20,0% 4 66,7% 20 43,5% 30N - 84V M46L 31 13,7% 17** 28,3% 2 9,5% 3 8,6% 3 17,6% 2 16,7% 0 0,0% 1 16,7% 3 6,5% I47V 14 6,2% 3 5,0% 3 14,3% 1 2,9% 2 11,8% 1 8,3% 0 0,0% 1 16,7% 2 4,3% 437V: G48V 13 5,8% 3 5,0% 2 9,5% 1 2,9% 1 5,9% 1 8,3% 1 10,0% 0 0,0% 1 2,2% 54V - 82F/T/S I50L/V 6 2,7% 1 1,7% 1 4,8% 2 5,7% 0 0,0% 0 0,0% 0 0,0% 0 0,0% 3 6,5% I54V 78 34,7% 31** 51,7% 8 38,1% 19* 54,3% 6 35,3% 5 41,7% 2 20,0% 2 33,3% 17 37,0% 449V: I54L/M/S/T/A 30 13,9% 7 11,7% 3 14,3% 6 17,1% 4 17,6% 5* 41,7% 1 0,0% 3 50,0% 6 13,0% 54L/M/S/T/A V82A 83 36,9% 34** 56,7% 10 47,6% 14 40,0% 5 29,4% 5 41,7% 2 20,0% 2 33,3% 9** 19,6% V82F/T/S 22 9,8% 7 11,7% 1 0,0% 10** 28,6% 0 0,0% 0 0,0% 2 20,0% 0 0,0% 4 8,7% 453L: I84V 49 21,7% 17 28,3% 2 9,5% 12 34,3% 8* 47,1% 3 25,0% 2 20,0% 3 50,0% 26** 56,5% 84V (82A) N88S/T 5 2,2% 2 3,3% 2 9,5% 1 2,9% 1 5,9% 0 0,0% 0 0,0% 0 0,0% 1 2,2% L90M 147 65,3% 35 58,3% 12 57,1% 23 65,7% 12 70,6% 8 66,7% 4 40,0% 6 100,0% 35 76,1% average primary PR 2,83+/-1,64 3,48+/-1,35 2,95+/-1,99 3,23+/-1,99 3,65+/-2,0 3,08+/-1,62 1,7+/-1,06 4,33+/-1,03 3,04+/-1,52 mutations Arevir 2009
Covariation analysis Arevir 2009 University of Cologne Institute of Virology
Bayesian netwerk using PR and gag mutations (PI failures) University of Cologne Institute of Virology Arevir 2009
Map of Cologne Arevir 2009 University of Cologne Institute of Virology
Prediction of therapy outcome for LPV containing therapy regimes University of Cologne Institute of Virology Prediction of therapy-outcome according the genotype during failure or before sustained suppression of viral replication. HIV CS-mutations: HIV CS-mutations: 431V, 436R, 437V, 431V, 437V, 449F 449F/V/H, 451T, 452S, 453A/L PR/RT 0,8386 PR/RT 0,8352 PR/RT/gag(group I) 0,8473 (p<0,01) PR/RT/gag(group II) 0,8511 (p<0,001) Arevir 2009
Conclusions University of Cologne Institute of Virology PI-resistence PR-mutations gag-CS-mutations Arevir 2009
Thank you! University of Cologne Institute of Virology Ulrike Schuldenzucker Europa Fachhochschule Fresenius, Cologne Bernd Kupfer Institute of Virology, University of Bonn Daniel Hoffmann Center for Medical Biotechnology, University of Duisburg-Essen Andre Altmann MPI for Informatics, Saarbrücken Alexander Thielen Thomas Lengauer Kristof Theys University of Leuven, Belgium Annemie Vandamme Martin Däumer Institute of Immunolgy and Genetik, Kaiserslautern Institute of Virology, University of Cologne Claudia Kücherer RKI, Berlin Elena Knops Maria Fraune Hauke Walter Nationales Referenzzentrum Retroviren, Nadine Sichtig Erlangen Eugen Schülter Claudia Müller Thomas Harrer Department of Medicine III, Sandra Müller University Hospital of Erlangen Dörte Hammerschmidt Monika Timmen-Wego Stefan Reuter Dept. of Gastroenterology, Saleta Sierra-Aragon University of Düsseldorf Eva Heger Finja Schweitzer Mark Oette Klösterchen hospital, Cologne Melanie Balduin Susanna Trapp Gerd Fätkenheuer Dept. of Internal Medicine I, Rolf Kaiser University of Cologne Herbert Pfister Arevir 2009 Jürgen Rockstroh Dept. of Internal Medicine I, University of Bonn
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