Surface-engineering of lentiviral vectors

Abstract

SummaryVectors derived from retroviridae offer particularly flexible properties in gene transfer applications given the numerous possible associations of various viral surface glycoproteins (determining cell tropism) with different types of retroviral cores (determining genome replication and integration). Lentiviral vectors should be preferred gene delivery vehicles over vectors derived from onco-retroviruses such as murine leukemia viruses (MLVs) that cannot transduce non-proliferating target cells. Generating lentiviral vectors pseudotyped with different viral glycoproteins (GPs) may modulate the physicochemical properties of the vectors, their interaction with the host immune system and their host range. There are however important gene transfer restrictions to some non-proliferative tissues or cell types and recent studies have shown that progenitor hematopoietic stem cells in G 0 , nonactivated primary blood lymphocytes or monocytes were not transducible by lentiviral vectors. Moreover, lentiviral vectors that have the capacity to deliver transgenes into specific tissues are expected to be of great value for various gene transfer applications in vivo. Several innovative approaches have been explored to overcome such problems that have given rise to novel concepts in the field and have provided promising results in preliminary evaluations in vivo. Here we review the different approaches explored to upgrade lentiviral vectors, aiming at developing vectors suitable for in vivo gene delivery.

Truncated vesicular stomatitis virus G protein improves baculovirus transduction efficiency in vitro and in vivo

“…These components are often derived from other viruses and have specific or wide tropism. 6 One of the most widely used pseudotyping tools is G glycoprotein of the vesicular stomatitis virus (VSV-G). [7][8][9][10] VSV-G is routinely used to enhance the target range and transduction efficiency of retroviruses 11 by providing wider tropism as well as improved viral stability and augmented resistance to the complement inactivation.…”

Prolonged Adherence of Human Immunodeficiency Virus-Derived Vector Particles to Hematopoietic Target Cells Leads to Secondary Transduction In Vitro and In Vivo

“…A wide range of Env glycoproteins are available for pseudotyping of recombinant retrovirus vector particles as a means of restricting species and tissue specificity, thereby allowing cellular targeting (40). Cell surface attachment of virus particles to target cells has also been shown to occur without receptor-ligand specificity (36), and most applications rely on serial wash steps after ex vivo exposure to remove bound, noninternalized particles prior to injection in animal models (19,29).…”

“…Human immunodeficiency virus (HIV)-derived recombinant vectors pseudotyped with the vesicular stomatitis virus G (VSV-G) Env glycoprotein provide an extended host range and have proven particularly well suited for the genetic modification of postmitotic tissues and rarely dividing cells (6,8,23,39,40). Their application for the stable modification of hematopoietic cell populations has permitted the development of ex vivo culture protocols that combine efficient transduction with retention of target stem cell properties (1,16,18,20,21,24).…”

Gene therapy targeting to tumor endothelium

“…49 Lentivirus has intrinsically low endothelial infectivity, but is commonly pseudotyped with a variety of nonretroviral glycoproteins derived from other viruses such as vesiculoviruses (VSV), lyssaviruses, hepadnaviridae, flaviviridae, paramyxoviridae, orthomyxoviruses, filoviruses and alphaviruses. 50 However, to date, it is not clear if any of these pseudotyped lentiviruses can target endothelium more selectively. 51 Retargeting using antibodies Antibodies can be used to bind specific receptors on tumor vasculature to enable specific targeting of vectors.…”