PI und gag mutations: e.g.: TMC114 Jens Verheyen Institute of - PowerPoint PPT Presentation

University of Cologne Institute of Virology PI und gag mutations: e.g.: TMC114 Jens Verheyen Institute of Virology, Köln Arevir 2007, caesar, Bonn

Background University of Cologne Institute of Virology Viral fitness Nijhuis et al. TMC114: PR and gag gag mutations PI-resistence: are reported PR and CS De Meyer et al. Doyon et al. 1980 1985 1990 1995 2000 2005 Maturation- Inhibitor PI Endeckung NRTI FI ante portas HIV NNRTI CCR5-Ant. Integrase-Inh. NRTI: nucleotide reverse transcriptase inhibtior FI: Fusion-Inhibitor PI: protease-inhibitor CS: Cleveage-site Arevir 2007, caesar, Bonn NNRTI: non-nucleotide reverse transcriptase inhibitor PR: protease

Arevir 2007, caesar, Bonn HIV-Genome University of Cologne Institute of Virology

Method University of Cologne Institute of Virology >1194 GATTGTACTGAGA GACAAGCTAATTTTTTAG G GAAAATCTGG CCTTCCCACAAG G G GA G G CCAG G GAATTTCCTTCAGAG CAGACCAGAG CCAACAGCCCCAACAGCCCCACCAG AAGAGAGCTTCAG GTTTGG G GA G GA GACAACAACTCCCTCTCAGAAG mainframe mainframe xxl xxl Arevir 2007, caesar, Bonn

In vitro selection of TMC114-resistant HIV-1 from wild type HIV-1 (exp 367) University of Cologne Institute of Virology • In experiment 367, the genotypic and phenotypic profiles of four viruses selected from HIV- 1/IIIB at increasing concentrations of TMC114 and the corresponding PR/RT and GAG/PR recombinant viruses were determined. • Three of the selected viruses had TMC114 FC >10 . • The mutations K70E, S37N, S37D and I85V accumulated in the PR. However, the corresponding recombinant PR/RT viruses all had TMC114 FC < 1 . • Mutations G123E, H124Y, M200I, V390D, R409K, E428K, A431D, I437D, Y441H, and S473P accumulated in the GAG gene, whereas the insertion between amino acids 453 and 454 (present in the initial HIV-1/IIIB strain) disappeared. The corresponding GAG/PR recombinant viruses had TMC114 FC ranging from 2 to 5.1 . de Meyer et al. Abstract 19, IHDRW 2006, Sitges TMC114-score (POWER-Studien): 50V, 54L/M, 76V, 84V 11I, 32I, 33F, 47V, 73S, 89V Arevir 2007, caesar, Bonn

TMC114 gag Mutationen in unserer Datenbank University of Cologne Institute of Virology 428K, 431D, 437D were not found in our gag database. 437V is a therapy-associated cleavage site mutation and a precursor mutation for 437D. 441H und 473P are natural polymorphisms. Arevir 2007, caesar, Bonn

Conclusions University of Cologne Institute of Virology PI, viral protease and cleavage sites are important for the evolution of PI resistance So far no TMC114 associated gag mutations have been seen in our database. After routinely administration of TMC114 in antiretroviral therapy, frequencies of gag mutations could possibly change. CS mutations should be considered in HIV genotypic resistance tests. Arevir 2007, caesar, Bonn

Interpretation von CS Mutationen?!? University of Cologne Institute of Virology mainframe mainframe xxl xxl 42 Arevir 2007, caesar, Bonn

Vielen Dank University of Cologne Institute of Virology Elena Litau Institute of Virology, University of Cologne Martin Däumer Melanie Balduin Saleta Sierra-Aragon Dörte Hammerschmidt Monika Timmen-Wego Rolf Kaiser Ulrike Schuldenzucker CAESAR, Bonn Daniel Hoffmann Center for Medical Biotechnology, University of Duisburg-Essen Tobias Sing MPI for Informatics, Saarbrücken Thomas Lengauer Hauke Walter Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg Mark Oette Dept. of Gastroenterology, University of Düsseldorf Gerd Fätkenheuer Dept. of Internal Medicine I, University of Cologne Jürgen K. Rockstroh Dept. of Internal Medicine I, University of Bonn Arevir 2007, caesar, Bonn