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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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Works referenced in this record:

Loss of Raltegravir Susceptibility by Human Immunodeficiency Virus Type 1 Is Conferred via Multiple Nonoverlapping Genetic Pathways
journal, September 2009

  • Fransen, S.; Gupta, S.; Danovich, R.
  • Journal of Virology, Vol. 83, Issue 22
  • DOI: 10.1128/JVI.01168-09

The HIV-1 Integrase Mutations Y143C/R Are an Alternative Pathway for Resistance to Raltegravir and Impact the Enzyme Functions
journal, April 2010


Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection
journal, July 2008

  • Cooper, David A.; Steigbigel, Roy T.; Gatell, Jose M.
  • New England Journal of Medicine, Vol. 359, Issue 4
  • DOI: 10.1056/NEJMoa0708978

HIV drug resistance against strand transfer integrase inhibitors
journal, June 2017


Switching between raltegravir resistance pathways analyzed by deep sequencing
journal, January 2011


Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection
journal, March 1998

  • Palella, Frank J.; Delaney, Kathleen M.; Moorman, Anne C.
  • New England Journal of Medicine, Vol. 338, Issue 13
  • DOI: 10.1056/NEJM199803263381301

Quantitative evaluation of the antiretroviral efficacy of dolutegravir
journal, November 2016


Evolution of raltegravir resistance during therapy
journal, May 2009

  • Sichtig, N.; Sierra, S.; Kaiser, R.
  • Journal of Antimicrobial Chemotherapy, Vol. 64, Issue 1
  • DOI: 10.1093/jac/dkp153

Fidelity of HIV-1 reverse transcriptase copying RNA in vitro
journal, February 1992


New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors
journal, April 2014

  • Malet, I.; Gimferrer Arriaga, L.; Artese, A.
  • Journal of Antimicrobial Chemotherapy, Vol. 69, Issue 8
  • DOI: 10.1093/jac/dku095

Dynamic escape of pre-existing raltegravir-resistant HIV-1 from raltegravir selection pressure
journal, December 2010


Use of dolutegravir in two INI-experienced patients with multiclass resistance resulted in excellent virological and immunological responses
journal, November 2014

  • Marije Hofstra, Laura; Nijhuis, Monique; Mudrikova, Tania
  • Journal of the International AIDS Society, Vol. 17
  • DOI: 10.7448/IAS.17.4.19755

Retroviral intasome assembly and inhibition of DNA strand transfer
journal, January 2010

  • Hare, Stephen; Gupta, Saumya Shree; Valkov, Eugene
  • Nature, Vol. 464, Issue 7286
  • DOI: 10.1038/nature08784

A novel real-time PCR assay to determine relative replication capacity for HIV-1 protease variants and/or reverse transcriptase variants
journal, May 2006


Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors
journal, March 2016

  • Brenner, Bluma G.; Thomas, Réjean; Blanco, José Luis
  • Journal of Antimicrobial Chemotherapy, Vol. 71, Issue 7
  • DOI: 10.1093/jac/dkw071

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study
journal, January 2014

  • Castagna, A.; Maggiolo, F.; Penco, G.
  • Journal of Infectious Diseases, Vol. 210, Issue 3
  • DOI: 10.1093/infdis/jiu051

Mutation Q95K enhances N155H-mediated integrase inhibitor resistance and improves viral replication capacity
journal, August 2010

  • Fun, A.; Van Baelen, K.; van Lelyveld, S. F. L.
  • Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 11
  • DOI: 10.1093/jac/dkq319

HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications
journal, May 2011

  • Blanco, Jose-Luis; Varghese, Vici; Rhee, Soo-Yon
  • The Journal of Infectious Diseases, Vol. 203, Issue 9
  • DOI: 10.1093/infdis/jir025

Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143
journal, January 2011


Anti-viral Drug Treatment: Dynamics of Resistance in Free Virus and Infected Cell Populations
journal, January 1997

  • Nowak, Martin A.; Bonhoeffer, Sebastian; Shaw, George M.
  • Journal of Theoretical Biology, Vol. 184, Issue 2
  • DOI: 10.1006/jtbi.1996.0307

Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy
journal, November 1998

  • Nijhuis, M.; Boucher, C. A. B.; Schipper, P.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 24
  • DOI: 10.1073/pnas.95.24.14441

Explosive ice age diversification of kiwi
journal, August 2016

  • Weir, Jason T.; Haddrath, Oliver; Robertson, Hugh A.
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 38
  • DOI: 10.1073/pnas.1603795113

Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo
journal, May 2009


Unequal human immunodeficiency virus type 1 reverse transcriptase error rates with RNA and DNA templates.
journal, August 1992

  • Boyer, J. C.; Bebenek, K.; Kunkel, T. A.
  • Proceedings of the National Academy of Sciences, Vol. 89, Issue 15
  • DOI: 10.1073/pnas.89.15.6919

Eutherian morphological disparity across the end-Cretaceous mass extinction
journal, December 2015

  • Halliday, Thomas John Dixon; Goswami, Anjali
  • Biological Journal of the Linnean Society, Vol. 118, Issue 1
  • DOI: 10.1111/bij.12731

Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing
journal, July 2010


Structure-based modeling of the functional HIV-1 intasome and its inhibition
journal, August 2010

  • Krishnan, L.; Li, X.; Naraharisetty, H. L.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 36
  • DOI: 10.1073/pnas.1002346107

Rapid and Durable Antiretroviral Effect of the HIV-1 Integrase Inhibitor Raltegravir as Part of Combination Therapy in Treatment-Naive Patients With HIV-1 Infection: Results of a 48-Week Controlled Study
journal, January 2007

  • Markowitz, Martin; Nguyen, Bach-Yen; Gotuzzo, Eduardo
  • JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 46, Issue 2
  • DOI: 10.1097/QAI.0b013e318157131c

HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase
journal, October 2000

  • Espeseth, A. S.; Felock, P.; Wolfe, A.
  • Proceedings of the National Academy of Sciences, Vol. 97, Issue 21
  • DOI: 10.1073/pnas.200139397

Effect of Raltegravir Resistance Mutations in HIV-1 Integrase on Viral Fitness
journal, January 2010


Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants
journal, November 2008


Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients
journal, February 2009

  • Malet, I.; Delelis, O.; Soulie, C.
  • Journal of Antimicrobial Chemotherapy, Vol. 63, Issue 4
  • DOI: 10.1093/jac/dkp014

Durable Efficacy and Safety of Raltegravir Versus Efavirenz When Combined With Tenofovir/Emtricitabine in Treatment-Naive HIV-1–Infected Patients: Final 5-Year Results From STARTMRK
journal, January 2013

  • Rockstroh, Jürgen K.; DeJesus, Edwin; Lennox, Jeffrey L.
  • JAIDS Journal of Acquired Immune Deficiency Syndromes, Vol. 63, Issue 1
  • DOI: 10.1097/QAI.0b013e31828ace69

High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors
journal, January 2010


Virus dynamics and drug therapy
journal, June 1997

  • Bonhoeffer, S.; May, R. M.; Shaw, G. M.
  • Proceedings of the National Academy of Sciences, Vol. 94, Issue 13
  • DOI: 10.1073/pnas.94.13.6971

Rates of evolutionary change in viruses: patterns and determinants
journal, March 2008

  • Duffy, Siobain; Shackelton, Laura A.; Holmes, Edward C.
  • Nature Reviews Genetics, Vol. 9, Issue 4
  • DOI: 10.1038/nrg2323

Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment
journal, December 2010

  • Liu, Jia; Miller, Michael D.; Danovich, Robert M.
  • Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 3
  • DOI: 10.1128/AAC.01492-10

Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy *
journal, October 2008


Low-frequency HIV-1 drug resistance mutations can be clinically significant but must be interpreted with caution
journal, May 2010

  • Johnson, J. A.; Geretti, A. M.
  • Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 7
  • DOI: 10.1093/jac/dkq139

Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics
journal, February 2009


Clinical Use of HIV Integrase Inhibitors: A Systematic Review and Meta-Analysis
journal, January 2013


HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens
journal, April 2010

  • da Silva, D.; Van Wesenbeeck, L.; Breilh, D.
  • Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 6
  • DOI: 10.1093/jac/dkq099

PCR-Induced Transitions Are the Major Source of Error in Cleaned Ultra-Deep Pyrosequencing Data
journal, July 2013


APE: Analyses of Phylogenetics and Evolution in R language
journal, January 2004


Pre-existence and emergence of drug resistance in a generalized model of intra-host viral dynamics
journal, December 2012


Mutations Associated with Failure of Raltegravir Treatment Affect Integrase Sensitivity to the Inhibitor In Vitro
journal, January 2008

  • Malet, I.; Delelis, O.; Valantin, M. -A.
  • Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 4
  • DOI: 10.1128/AAC.01228-07

Human immunodeficiency virus type 1 drug susceptibility determination by using recombinant viruses generated from patient sera tested in a cell-killing assay.
journal, October 1996

  • Boucher, C. A.; Keulen, W.; van Bommel, T.
  • Antimicrobial Agents and Chemotherapy, Vol. 40, Issue 10
  • DOI: 10.1128/AAC.40.10.2404

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