Prevalence of therapy-associated HIV gag CS mutations Jens Verheyen - - PowerPoint PPT Presentation

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prevalence of therapy associated hiv gag cs mutations

Prevalence of therapy-associated HIV gag CS mutations Jens Verheyen - - PowerPoint PPT Presentation

Oct 21, 2022 354 likes •492 views

University of Cologne Institute of Virology Prevalence of therapy-associated HIV gag CS mutations Jens Verheyen Institut fr Virologie Uniklinik Kln Arevir 2009 HIV replication and drugs University of Cologne Institute of Virology

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Arevir 2009

University of Cologne Institute of Virology

Prevalence of therapy-associated HIV gag CS mutations

Jens Verheyen

Institut für Virologie Uniklinik Köln

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Arevir 2009

University of Cologne Institute of Virology

HIV replication and drugs

Viruseintritt in die Zelle: Fusions-Inhibitor Corezeptor-Blocker Reverse Transkription: NRTIs, NNRTIs Nukleosidische und Nichtnukleosidische Reverse Transkriptase Inhibitoren Maturation: Protease-Inhibitoren Integration proviraler DNA: Integrase-Inhibitoren

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Arevir 2009

University of Cologne Institute of Virology

Protease - Substrat - Medikamente

Viral protease Protease-Inhibitor Precursor proteins gag gag-pol

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Arevir 2009

University of Cologne Institute of Virology

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

Therapy-associated HIV gag CS mutations

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Arevir 2009

University of Cologne Institute of Virology

Prevalence of HIV gag CS mutations in PI resistant HIV isolates

Major- PR mutations: 24I, 32I, 46I/L, 50V/L, 54V/L/M/S/T/A, 82A/F/T/S, 84V, 90M Percent of CS positive HIV

13,5 25,8 40,0 63,3 86,9 87,5 93,8 20 40 60 80 100 without prim. Resistance with prim. Resistance 1 major PR 2 major PR 3 major PR 4 major PR 5 major PR TN-HIV TE-HIV

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Arevir 2009

University of Cologne Institute of Virology

Correlation between HIV gag CS and PR mutations

n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) n= (% ) L24I 23 10,1% 14** 23,3% 1 4,8% 3 8,6% 3 17,6% 1 8,3% 0,0% 0,0% 2 4,3% D30N 18 7,9% 0** 0,0% 2 9,5% 1 2,9% 4* 23,5% 0,0% 0,0% 0,0% 7 15,2% V32I 21 9,3% 2 3,3% 4 19,0% 1 2,9% 2 11,8% 1 8,3% 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% 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% M46L 31 13,7% 17** 28,3% 2 9,5% 3 8,6% 3 17,6% 2 16,7% 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% 1 16,7% 2 4,3% G48V 13 5,8% 3 5,0% 2 9,5% 1 2,9% 1 5,9% 1 8,3% 1 10,0% 0,0% 1 2,2% I50L/V 6 2,7% 1 1,7% 1 4,8% 2 5,7% 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% 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% 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% 2 20,0% 0,0% 4 8,7% 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% N88S/T 5 2,2% 2 3,3% 2 9,5% 1 2,9% 1 5,9% 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 mutations P453A 6 P453L * 46 2,83+/-1,64 2,95+/-1,99 3,48+/-1,35 3,65+/-2,0 3,08+/-1,62 4,33+/-1,03 3,04+/-1,52 1,7+/-1,06 225 A431V K436R 21 all TE- viruses 60 I437V 35 L449F 17 3,23+/-1,99 L449V 12 L449P 10

431V: 24I - 46I - 46L - 54V - 82A (30N) 449F: 30N - 84V 437V: 54V - 82F/T/S 449V: 54L/M/S/T/A 453L: 84V (82A)

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Arevir 2009

University of Cologne Institute of Virology

Covariation analysis

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Arevir 2009

University of Cologne Institute of Virology

Bayesian netwerk using PR and gag mutations (PI failures)

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Arevir 2009

University of Cologne Institute of Virology

Map of Cologne

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Arevir 2009

University of Cologne Institute of Virology

Prediction of therapy outcome for LPV containing therapy regimes

PR/RT 0,8386 PR/RT/gag(group I) 0,8473 (p<0,01) PR/RT 0,8352 PR/RT/gag(group II) 0,8511 (p<0,001) HIV CS-mutations: 431V, 437V, 449F HIV CS-mutations: 431V, 436R, 437V, 449F/V/H, 451T, 452S, 453A/L

Prediction of therapy-outcome according the genotype during failure or before sustained suppression of viral replication.

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Arevir 2009

University of Cologne Institute of Virology

Conclusions

PI-resistence PR-mutations gag-CS-mutations

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Arevir 2009

University of Cologne Institute of Virology

Thank you!

Institute of Virology, University of Cologne Elena Knops Maria Fraune Nadine Sichtig Eugen Schülter Claudia Müller Dörte Hammerschmidt Monika Timmen-Wego Saleta Sierra-Aragon Eva Heger Finja Schweitzer Melanie Balduin Susanna Trapp Rolf Kaiser Herbert Pfister

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 Claudia Kücherer RKI, Berlin Hauke Walter Nationales Referenzzentrum Retroviren, Erlangen Thomas Harrer Department of Medicine III, Sandra Müller University Hospital of Erlangen Stefan Reuter Dept. of Gastroenterology, University of Düsseldorf Mark Oette Klösterchen hospital, Cologne Gerd Fätkenheuer

Dept. of Internal Medicine I,

University of Cologne Jürgen Rockstroh

Dept. of Internal Medicine I, University of Bonn