HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects (original) (raw)

Nature Medicine volume 16, pages 460–465 (2010)Cite this article

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Abstract

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted1,2. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels3, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs4,5. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

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Acknowledgements

We are grateful to the Integral study group members R. Escrig, M. Larús, I. Bravo and J. Puig for clinical monitoring during the study and to R. Ayén, T. González and E. Grau for sample processing. We thank N. Hosoya and D.R. Kuritzkes (Massachusetts General Hospital, Boston) for providing the plasmid to generate the standard for the integrated HIV-1 DNA quantification. We wish to thank the volunteers who participated in this study. This study was supported by the Spanish AIDS network 'Red Temática Cooperativa de Investigación en SIDA' (RD06/0006), by funding from the European Community's Seventh Framework Program (FP7/2007-2013) under the Collaborative HIV and Anti-HIV Drug Resistance Network grant agreement 223131, by funding from the US National Institutes of Health to M. Stevenson and by an unrestricted grant from Merck Sharp & Dohme. J.B. is a researcher from Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol supported by the Instituto de Salud Carlos III and the Health Department of the Catalan Government (Generalitat de Catalunya). M.J.B. and M.M. were supported by Agència de Gestió d'Ajuts Universitaris i de Recerca from Generalitat de Catalunya and the European Social Fund. M.M. is appointed to the Pompeu Fabra University PhD program. S.P. was funded, in part, by the Swedish Research Council and by 107170-44-RGRL from the Foundation for AIDS Research.

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Author notes

  1. Maria J Buzón and Marta Massanella: These authors contributed equally to this work.

Authors and Affiliations

  1. irsiCaixa Foundation, Institut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
    Maria J Buzón, Marta Massanella, Maria C Puertas, Roger Paredes, Bonaventura Clotet, Julià Blanco & Javier Martinez-Picado
  2. 'Lluita contra la SIDA' Foundation, Badalona, Spain
    Josep M Llibre, Roger Paredes & Bonaventura Clotet
  3. Center for Epidemiological Studies on STI and HIV/AIDS of Catalonia, Badalona, Spain
    Anna Esteve
  4. Swedish Institute for Infectious Disease Control, Solna, Sweden
    Viktor Dahl & Sarah Palmer
  5. Hospital Clínic-Idibaps, Barcelona, Spain
    Josep M Gatell
  6. Hospital Sant Pau, Barcelona, Spain
    Pere Domingo
  7. University of Massachusetts Medical School, Worcester, Massachusetts, USA
    Mark Sharkey & Mario Stevenson
  8. Catalan Institution for Research and Advanced Studies, Barcelona, Spain
    Javier Martinez-Picado

Authors

  1. Maria J Buzón
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  2. Marta Massanella
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  3. Josep M Llibre
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  4. Anna Esteve
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  5. Viktor Dahl
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  6. Maria C Puertas
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  7. Josep M Gatell
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  8. Pere Domingo
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  9. Roger Paredes
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  10. Mark Sharkey
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  11. Sarah Palmer
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  12. Mario Stevenson
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  13. Bonaventura Clotet
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  14. Julià Blanco
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  15. Javier Martinez-Picado
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Contributions

M.J.B. and M.M. designed, executed and interpreted most experiments and prepared the manuscript. J.M.L. designed the study and participated in subject recruitment and clinical care. A.E. performed statistical analyses. V.D. executed single-copy assays. M.C.P. helped with real-time PCR experiments. J.M.G. and P.D. participated in subject recruitment and clinical care. R.P. contributed in experimental design. M. Sharkey helped in experimental setup and provided reagents. S.P. executed single-copy assays. M. Stevenson provided interpretation of the data and helped with the manuscript preparation. B.C. designed the study, participated in subject recruitment and clinical care and provided interpretation of the data. J.B. supervised immunological experiments, data interpretation and participated in manuscript preparation. J.M.-P. supervised all aspects of this study including study design, execution and interpretation and manuscript preparation.

Corresponding author

Correspondence toJavier Martinez-Picado.

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Competing interests

J.M.L. has received research funding, consultancy fees or lecture sponsorships from Abbott, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck, Pfizer and Roche. R.P. has received grant support or lecture fees from Boehringer-Ingelheim, Monogram, Pfizer, Merck and Siemens Medical Solutions. M.S. has been a consultant for Merck and has received research support from Tibotec. J.M.G. has received grant support or lecture or advisory fees from Merck, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Tibotec, Pfizer, Gilead, Abbott and Boehringer Ingelheim. B.C. has served as a consultant on advisory boards, participated in speakers' bureaus or conducted clinical trials with Roche, Boehringer-Ingelheim, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Tibotec, Janssen, Merck, Pfizer, Siemens, Monogram Biosciences and Panacos. J.M.-P. has received research funding, consultancy fees, or lecture sponsorships from GlaxoSmithKline, Merck and Roche.

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J Buzón, M., Massanella, M., Llibre, J. et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects.Nat Med 16, 460–465 (2010). https://doi.org/10.1038/nm.2111

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