Should HIV-1 Gag mutations be included in genotypic drug resistance - - PowerPoint PPT Presentation

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Sep 28, 2023 486 likes •691 views

University of Cologne Institute of Virology Should HIV-1 Gag mutations be included in genotypic drug resistance scores? Jens Verheyen, MD Institute of Virology University of Cologne Triangle: patients - HAART - HIV University of Cologne

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University of Cologne Institute of Virology

Should HIV-1 Gag mutations be included in genotypic drug resistance scores?

Jens Verheyen, MD

Institute of Virology University of Cologne

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University of Cologne Institute of Virology

Triangle: patients - HAART - HIV

HIV-1 antiretroviral treatment patient

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University of Cologne Institute of Virology

Duo: HAART - HIV-1

HIV-1 antiretroviral treatment patient

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University of Cologne Institute of Virology

Duo: protease inhibitors - protease

protease protease inhibitor patient

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University of Cologne Institute of Virology

protease protease inhibitor patient

Triangle: protease inhibitors - protease - substrate

precursor proteins

X X X X X X X X

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University of Cologne Institute of Virology

Genotypic HIV-1 drug resistance assays

HIV-1 genome

All routine genotypic resistance tests include: C-terminal gag, the protease, and the reverse transcriptase 2006-2011: 1268 (one HIV-1 genotype per patient) TN HIV-1 without primary resistance: 608 TN HIV-1 with primary resistance: 75 TE HIV-1 with PR mutations: 199 PI failure: 240

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University of Cologne Institute of Virology

Treatment naive HIV-1 isolates

E428D, A431VI, K436N, I437V, L449FHV, S451T, R452S, P453AL

Gag CS mutations were significantly correlated with PR mutations Frequency of Gag CS mutations: TN 14% TN+any primary Resistance 20% TN+primary PI Resistance 43% TE+any PR mutation 59% TE+1PR 30% TE+2PR 71% TE+3PR 81% TE+4PR 85% TE+>5PR 79%

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University of Cologne Institute of Virology

Summary I:

Gag CS and PR mutations accumulated in PI resistant HIV-1 isolates Gag CS and PR mutations present two sites of the same coin HIV-1 PI resistance

PR mutations Gag CS mutations

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University of Cologne Institute of Virology

Gag CS mutations and treatment failure

HIV-1 genotypes were obtained at least 60 days after the start antiretroviral treatment with protease inhibitors (n=240).

PI failure without PR mutations: n=178 (74%) PI failure without PR mutations + Gag CS mutations n=17 (7.4%) PI failure without PR mutations + Gag CS mutations + RT mutations n=6 (2.5%) PI failure (double PI) 1 PR + Gag CS mutations n=2 (0.8%)

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University of Cologne Institute of Virology

CS mutations and treatment failure

Intermediate PI resistance level => 1-4 PR mutations => 30-80% Gag CS mutations PR and Gag CS mutations might explain treatment failure

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University of Cologne Institute of Virology

Summary II

Protease and Gag CS-mutations are also correlated with PI treatment failure

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University of Cologne Institute of Virology

Should HIV-1 Gag mutations be included in genotypic drug resistance scores? Yes, we should!

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University of Cologne Institute of Virology

Genotypic HIV-1 drug resistance assay ABI sequencing kit HIV-1 (Abbott)

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University of Cologne Institute of Virology

http://www.geno2pheno.org/

geno2phenogag

>6919 AAGATTGTACTGAGAGACAGGTTAATTTTTTAGGGAAGGTCTGGCC TTCCCACAAAGGAAGGCCAGGGAACTTTTTTCAGACCAGCCTAGAG CCAACAGCCCCACCAGCAGAGAGCTTCATGTTCGGGGGGGAGA

Output (rules based):

1. Subtype (Similarity)
2. Scoring of PI-related

Gag mutations

3. Scoring of mutations

locates in CTL epitopes.

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University of Cologne Institute of Virology

Should HIV-1 Gag mutations be included in genotypic drug resistance scores? Yes, we should! Yes, we can!

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University of Cologne Institute of Virology

In the future New sequence technologies HIV-1 whole genome sequencing

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University of Cologne Institute of Virology

Should HIV-1 Gag mutations be included in genotypic drug resistance scores? Yes, we should! Yes, we can! Yes, we will!

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University of Cologne Institute of Virology

Thank you!

Institute of Virology, University of Cologne Elena Knops Maria Neumann-Fraune Nadine Lübke Eugen Schülter Claudia Müller Dörte Hammerschmidt Monika Timmen-Wego Saleta Sierra-Aragon Eva Heger Finja Schweitzer Rolf Kaiser Herbert Pfister Daniel Hoffmann Center for Medical Biotechnology, Dominik Heider University of Duisburg-Essen Andre Altmann MPI for Informatics, Saarbrücken Alejandro Pironti Alexander Thielen Thomas Lengauer Gerd Fätkenheuer

Dept. of Internal Medicine I, University of Cologne

Mark Oette Clinic of General Medicine, Augustinerinnen Hospital Stefan Reuter Clinic of Gastr. Hepat. And Infect Dis., Björn Jenssen University of Duesseldorf