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Title: Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance

Abstract

Background Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is typically associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We reviewed the effect of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks. Results Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist ofmore » a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture. Conclusions The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.« less

Authors:
 [1]; ORCiD logo [2];  [3];  [4];  [5];  [6];  [1];  [7];  [1];  [1];  [1]
  1. Univ. of Utrecht (Netherlands)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Ghent Univ. (Belgium)
  4. Inst. of Immunology and Genetics, Kaiserslautern (Germany)
  5. Max Planck Inst. for Informatics, Saarbrücken (Germany)
  6. Univ. Mannheim (Germany)
  7. Rijnstate Hospital, Arnhem (Netherlands)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); Dutch AIDS Fund; Netherlands Organization for Scientific Research, National Institutes of Health (NIH)
OSTI Identifier:
1558074
Report Number(s):
LA-UR-19-25852
Journal ID: ISSN 1742-4690
Grant/Contract Number:  
89233218CNA000001
Resource Type:
Accepted Manuscript
Journal Name:
Retrovirology
Additional Journal Information:
Journal Volume: 15; Journal Issue: 1; Journal ID: ISSN 1742-4690
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Fun, Axel, Leitner, Thomas, Vandekerckhove, Linos, Däumer, Martin, Thielen, Alexander, Buchholz, Bernd, Hoepelman, Andy I. M., Gisolf, Elizabeth H., Schipper, Pauline J., Wensing, Annemarie M. J., and Nijhuis, Monique. Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance. United States: N. p., 2018. Web. doi:10.1186/s12977-017-0384-z.
Fun, Axel, Leitner, Thomas, Vandekerckhove, Linos, Däumer, Martin, Thielen, Alexander, Buchholz, Bernd, Hoepelman, Andy I. M., Gisolf, Elizabeth H., Schipper, Pauline J., Wensing, Annemarie M. J., & Nijhuis, Monique. Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance. United States. doi:10.1186/s12977-017-0384-z.
Fun, Axel, Leitner, Thomas, Vandekerckhove, Linos, Däumer, Martin, Thielen, Alexander, Buchholz, Bernd, Hoepelman, Andy I. M., Gisolf, Elizabeth H., Schipper, Pauline J., Wensing, Annemarie M. J., and Nijhuis, Monique. Fri . "Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance". United States. doi:10.1186/s12977-017-0384-z. https://www.osti.gov/servlets/purl/1558074.
@article{osti_1558074,
title = {Impact of the HIV-1 genetic background and HIV-1 population size on the evolution of raltegravir resistance},
author = {Fun, Axel and Leitner, Thomas and Vandekerckhove, Linos and Däumer, Martin and Thielen, Alexander and Buchholz, Bernd and Hoepelman, Andy I. M. and Gisolf, Elizabeth H. and Schipper, Pauline J. and Wensing, Annemarie M. J. and Nijhuis, Monique},
abstractNote = {Background Emergence of resistance against integrase inhibitor raltegravir in human immunodeficiency virus type 1 (HIV-1) patients is typically associated with selection of one of three signature mutations: Y143C/R, Q148K/H/R or N155H, representing three distinct resistance pathways. The mechanisms that drive selection of a specific pathway are still poorly understood. We reviewed the effect of the HIV-1 genetic background and population dynamics on the emergence of raltegravir resistance. Using deep sequencing we analyzed the integrase coding sequence (CDS) in longitudinal samples from five patients who initiated raltegravir plus optimized background therapy at viral loads > 5000 copies/ml. To investigate the role of the HIV-1 genetic background we created recombinant viruses containing the viral integrase coding region from pre-raltegravir samples from two patients in whom raltegravir resistance developed through different pathways. The in vitro selections performed with these recombinant viruses were designed to mimic natural population bottlenecks. Results Deep sequencing analysis of the viral integrase CDS revealed that the virological response to raltegravir containing therapy inversely correlated with the relative amount of unique sequence variants that emerged suggesting diversifying selection during drug pressure. In 4/5 patients multiple signature mutations representing different resistance pathways were observed. Interestingly, the resistant population can consist of a single resistant variant that completely dominates the population but also of multiple variants from different resistance pathways that coexist in the viral population. We also found evidence for increased diversification after stronger bottlenecks. In vitro selections with low viral titers, mimicking population bottlenecks, revealed that both recombinant viruses and HXB2 reference virus were able to select mutations from different resistance pathways, although typically only one resistance pathway emerged in each individual culture. Conclusions The generation of a specific raltegravir resistant variant is not predisposed in the genetic background of the viral integrase CDS. Typically, in the early phases of therapy failure the sequence space is explored and multiple resistance pathways emerge and then compete for dominance which frequently results in a switch of the dominant population over time towards the fittest variant or even multiple variants of similar fitness that can coexist in the viral population.},
doi = {10.1186/s12977-017-0384-z},
journal = {Retrovirology},
number = 1,
volume = 15,
place = {United States},
year = {2018},
month = {1}
}

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