Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells

Blood. 2014 Aug 7;124(6):913-23. doi: 10.1182/blood-2013-12-546218. Epub 2014 Jun 9.


Transplantation of genetically modified hematopoietic stem cells (HSCs) is a promising therapeutic strategy for genetic diseases, HIV, and cancer. However, a barrier for clinical HSC gene therapy is the limited efficiency of gene delivery via lentiviral vectors (LVs) into HSCs. We show here that rapamycin, an allosteric inhibitor of the mammalian target of rapamycin complexes, facilitates highly efficient lentiviral transduction of mouse and human HSCs and dramatically enhances marking frequency in long-term engrafting cells in mice. Mechanistically, rapamycin enhanced postbinding endocytic events, leading to increased levels of LV cytoplasmic entry, reverse transcription, and genomic integration. Despite increasing LV copy number, rapamycin did not significantly alter LV integration site profile or chromosomal distribution in mouse HSCs. Rapamycin also enhanced in situ transduction of mouse HSCs via direct intraosseous infusion. Collectively, rapamycin strongly augments LV transduction of HSCs in vitro and in vivo and may prove useful for therapeutic gene delivery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genetic Vectors / drug effects
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / virology
  • Heterografts
  • Humans
  • Lentivirus / drug effects*
  • Lentivirus / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transduction, Genetic / methods*
  • Virus Internalization / drug effects


  • TOR Serine-Threonine Kinases
  • Sirolimus