Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity
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Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity. / Karpinski, Janet; Hauber, Ilona; Chemnitz, Jan; Schäfer, Carola; Paszkowski-Rogacz, Maciej; Chakraborty, Deboyoti; Beschorner, Niklas; Hofmann-Sieber, Helga; Lange, Ulrike C; Grundhoff, Adam; Hackmann, Karl; Schrock, Evelin; Abi-Ghanem, Josephine; Pisabarro, M Teresa; Surendranath, Vineeth; Schambach, Axel; Lindner, Christoph; van Lunzen, Jan; Hauber, Joachim; Buchholz, Frank.
In: NAT BIOTECHNOL, Vol. 34, No. 4, 04.2016, p. 401-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity
AU - Karpinski, Janet
AU - Hauber, Ilona
AU - Chemnitz, Jan
AU - Schäfer, Carola
AU - Paszkowski-Rogacz, Maciej
AU - Chakraborty, Deboyoti
AU - Beschorner, Niklas
AU - Hofmann-Sieber, Helga
AU - Lange, Ulrike C
AU - Grundhoff, Adam
AU - Hackmann, Karl
AU - Schrock, Evelin
AU - Abi-Ghanem, Josephine
AU - Pisabarro, M Teresa
AU - Surendranath, Vineeth
AU - Schambach, Axel
AU - Lindner, Christoph
AU - van Lunzen, Jan
AU - Hauber, Joachim
AU - Buchholz, Frank
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
U2 - 10.1038/nbt.3467
DO - 10.1038/nbt.3467
M3 - SCORING: Journal article
C2 - 26900663
VL - 34
SP - 401
EP - 409
JO - NAT BIOTECHNOL
JF - NAT BIOTECHNOL
SN - 1087-0156
IS - 4
ER -