Efficiency of Lentiviral Vectors Pseudotyped with LCMV-G in Gene Transfer to Ldlr−/−ApoB100/100 Mice

TL;DR

This study compares the efficiency of lentiviral vectors pseudotyped with LCMV glycoprotein versus VSV-G in gene transfer to mice lacking LDL receptors.

Contribution

The study demonstrates that LCMV-LVs can be an effective alternative to VSV-G-LVs, though they may require higher doses for comparable gene transfer efficiency.

Findings

LCMV-LVs transduced all tested cell types efficiently in vitro without enhancers.

VSV-G-LVs showed higher in vivo gene transfer efficiency at the same dose, but LCMV-LVs accumulated more in the lungs.

A high-fat diet reduced the gene transfer efficiency of LCMV-LVs.

Abstract

Background/Objectives: Lentiviral vectors (LVs) are most commonly pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G), which lends LVs a wide tropism as it uses the low-density lipoprotein receptor (LDLR) as the main receptor for cell entry. In some gene therapy and research applications, however, alternative pseudotypes can be useful. In this work, we characterized LVs pseudotyped with lymphocytic choriomeningitis virus (LCMV) glycoprotein, particularly in gene transfer to an LDLR-deficient mouse strain used to model cardiovascular disease, Ldlr−/−ApoB100/100. Methods: LCMV-LVs were used in vitro to test their transduction efficiency across a variety of cell types. In vivo, the gene transfer efficiency, LV-specific immune responses and biodistribution of VSV-G-LVs and LCMV-LVs were compared after systemic gene transfer. Results: In vitro, LCMV-LVs transduced all tested cell types at high efficiency without the use of transduction enhancers. In vivo, VSV-G-LVs showed a higher gene transfer efficiency at the same LV dose, but increasing the LCMV-LV dose enhanced the measured vector copy numbers. With both pseudotypes, most of the vector accrued in the liver, but with LCMV-LVs, a larger portion of the measured vector copies were found in the lungs. VSV-G-LVs also generated a higher titer of LV-specific IgG antibodies. The gene transfer efficiency of LCMV-LVs was affected by the mouse diet, with a high-fat diet decreasing the transduction. Conclusions: LCMV-LVs can be used as a substitute for VSV-G-LVs if an alternative pseudotype is required; however, they may require the use of a higher LV dose.

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