Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Janet Karpinski - , Medizinische Systembiologie, Universitätsklinikum Carl Gustav Carus Dresden (Erstautor:in)
  • Ilona Hauber - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Erstautor:in)
  • Jan Chemnitz - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Erstautor:in)
  • Carola Schäfer - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Maciej Paszkowski-Rogacz - , Medizinische Systembiologie, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Deboyoti Chakraborty - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Niklas Beschorner - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Helga Hofmann-Sieber - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Ulrike C Lange - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology, Deutsche Zentrum für Infektionsforschung, Universität Hamburg (Autor:in)
  • Adam Grundhoff - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Karl Hackmann - , Institut für Klinische Genetik, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Evelin Schrock - , Institut für Klinische Genetik (Autor:in)
  • Josephine Abi-Ghanem - , Strukturelle Bioinformatik (FoG), Biotechnologisches Zentrum (BIOTEC) (Autor:in)
  • M Teresa Pisabarro - , Strukturelle Bioinformatik (FoG), Biotechnologisches Zentrum (BIOTEC) (Autor:in)
  • Vineeth Surendranath - , Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)
  • Axel Schambach - , Institute of Experimental Hematology (Autor:in)
  • Christoph Lindner - , Agaplesion Diakonieklinikum Hamburg (Autor:in)
  • Jan van Lunzen - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Joachim Hauber - , Heinrich Pette Institute - Leibniz Institute for Experimental Virology (Autor:in)
  • Frank Buchholz - , Medizinische Systembiologie, Universitätsklinikum Carl Gustav Carus Dresden, Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)

Abstract

Current combination antiretroviral therapies (cART) efficiently suppress HIV-1 reproduction in humans, but the virus persists as integrated proviral reservoirs in small numbers of cells. To generate an antiviral agent capable of eradicating the provirus from infected cells, we employed 145 cycles of substrate-linked directed evolution to evolve a recombinase (Brec1) that site-specifically recognizes a 34-bp sequence present in the long terminal repeats (LTRs) of the majority of the clinically relevant HIV-1 strains and subtypes. Brec1 efficiently, precisely and safely removes the integrated provirus from infected cells and is efficacious on clinical HIV-1 isolates in vitro and in vivo, including in mice humanized with patient-derived cells. Our data suggest that Brec1 has potential for clinical application as a curative HIV-1 therapy.

Details

OriginalspracheEnglisch
Seiten (von - bis)401-9
Seitenumfang9
FachzeitschriftNature Biotechnology
Jahrgang34
Ausgabenummer4
PublikationsstatusVeröffentlicht - Apr. 2016
Peer-Review-StatusJa

Externe IDs

researchoutputwizard legacy.publication#73553
PubMed 26900663
Scopus 84963553372

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Animals, Antiviral Agents/metabolism, Base Sequence, Cells, Cultured, Directed Molecular Evolution/methods, HIV Infections/virology, HIV-1/drug effects, Humans, Mice, Molecular Sequence Data, Proviruses/drug effects, Recombinases/metabolism, Virus Integration/drug effects