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Nat Biotechnol. 2016 Apr;34(4):401-9. doi: 10.1038/nbt.3467. Epub 2016 Feb 22.

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

Author information

1
Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Germany.
2
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
3
German Center for Infection Research (DZIF), partner site Hamburg, Germany.
4
Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Institute for Clinical Genetics, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden, Germany.
6
Structural Bioinformatics, BIOTEC TU Dresden, Germany.
7
Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
8
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
9
Agaplesion Diakonieklinikum, Gynecology, Hamburg, Germany.
10
Infectious Diseases Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.

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PMID:
26900663
DOI:
10.1038/nbt.3467
[Indexed for MEDLINE]

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