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

▶

Feb 24, 2023 217 likes •330 views

University of Cologne Institute of Virology PI und gag mutations: e.g.: TMC114 Jens Verheyen Institute of Virology, Kln Arevir 2007, caesar, Bonn Background University of Cologne Institute of Virology Viral fitness Nijhuis et al.

SLIDE 1

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

PI und gag mutations: e.g.: TMC114

Jens Verheyen Institute of Virology, Köln

SLIDE 2

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

NNRTI

Background

1980 1985 1990 1995 2000 2005 PI NRTI Endeckung HIV Integrase-Inh. FI CCR5-Ant. Maturation- Inhibitor ante portas

NRTI: nucleotide reverse transcriptase inhibtior PI: protease-inhibitor NNRTI: non-nucleotide reverse transcriptase inhibitor FI: Fusion-Inhibitor CS: Cleveage-site PR: protease

PI-resistence: PR and CS

Doyon et al.

TMC114: PR and gag mutations are reported

De Meyer et al.

Viral fitness

gag

Nijhuis et al.

SLIDE 3

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

HIV-Genome

SLIDE 4

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

Method

>1194 GATTGTACTGAGA GACAAGCTAATTTTTTAG G GAAAATCTGG CCTTCCCACAAG G G GA G G CCAG G GAATTTCCTTCAGAG CAGACCAGAG CCAACAGCCCCAACAGCCCCACCAG AAGAGAGCTTCAG GTTTGG G GA G GA GACAACAACTCCCTCTCAGAAG

mainframe xxl mainframe xxl

SLIDE 5

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

In vitro selection of TMC114-resistant HIV-1 from wild type HIV-1 (exp 367)

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

SLIDE 6

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

TMC114 gag Mutationen in unserer Datenbank

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.

SLIDE 7

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

Conclusions

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.

SLIDE 8

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

Interpretation von CS Mutationen?!?

mainframe xxl mainframe xxl

42

SLIDE 9

Arevir 2007, caesar, Bonn

University of Cologne Institute of Virology

Vielen Dank

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