Stable transduction of quiescent T cells without induction of cycle progression by a novel lentiviral vector pseudotyped with measles virus glycoproteins

Blood. 2008 Dec 15;112(13):4843-52. doi: 10.1182/blood-2008-05-155945. Epub 2008 Sep 23.

Abstract

A major limitation of current lentiviral vectors (LVs) is their inability to govern efficient gene transfer into quiescent cells such as primary T cells, which hampers their application for gene therapy. Here we generated high-titer LVs incorporating Edmonston measles virus (MV) glycoproteins H and F on their surface. They allowed efficient transduction through the MV receptors, SLAM and CD46, both present on blood T cells. Indeed, these H/F-displaying vectors outperformed by far VSV-G-LVs for the transduction of IL-7-prestimulated T cells. More importantly, a single exposure to these H/F-LVs allowed efficient gene transfer in quiescent T cells, which are not permissive for VSV-G-LVs that need cell-cycle entry into the G1b phase for efficient transduction. High-level transduction of resting memory (50%) and naive (11%) T cells with H/F-LVs, which seemed to occur mainly through SLAM, was not at cost of cell-cycle entry or of target T-cell activation. Finally, the naive or memory phenotypes of transduced resting T cells were maintained and no changes in cytokine profiles were detected, suggesting that T-cell populations were not skewed. Thus, H/F-LV transduction of resting T cells overcomes the limitation of current lentiviral vectors and may improve the efficacy of T cell-based gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle*
  • Cell Line, Tumor
  • Cells, Cultured
  • Genetic Vectors*
  • Glycoproteins / genetics
  • Humans
  • Lentivirus / genetics*
  • Leukocytes
  • Measles virus / chemistry
  • Measles virus / genetics*
  • Receptors, Virus / metabolism
  • T-Lymphocytes / metabolism*
  • Transduction, Genetic / methods*
  • Viral Envelope Proteins / genetics

Substances

  • Glycoproteins
  • Receptors, Virus
  • Viral Envelope Proteins