Retroviruses in Human Gene Therapy

Abstract

A retrovirus‐based gene transfer system consists of two components: the transfer vector, which harbours a foreign gene linked to elements needed for retroviral replication, and the packaging constructs, which supply the necessary retroviral proteins for transfer of the vector from a producer cell through a single round of viral replication. A hallmark of retroviral replication is the stable maintenance of the transferred gene(s) during cell division. The first type of transfer vectors used in gene therapy trials were derived from mouse retroviruses and referred to as retroviral vectors. Lentiviral vectors are derived from human immunodeficiency virus type 1 and exhibit distinct features that provide advantages in some settings. Retroviral and lentiviral vectors are being used in clinical trials for several diseases, including monogenic diseases and cancer. The clinical protocols include primarily ex vivo gene transfer followed by introduction of the genetically modified cells into the body. Key Concepts The retroviral replication machinery leads to stable maintenance of a transferred gene. The stable integration of retroviral vectors into a chromosome of the target cell may have adverse effects on neighbouring genes. Retroviral gene transfer does not require the expression of retroviral genes in the target cell. The term retroviral vector is used for a vector based on murine leukaemia virus. The term lentiviral vector is used for a vector based on human immunodeficiency virus type 1. Retroviral and lentiviral vectors differ in their integration patterns with respect to genes and gene regulatory regions. To treat inherited monogenic disease affecting e.g. skin or blood, stem cells can be corrected ex vivo by using retroviral and lentiviral vectors. Retroviral and lentiviral vectors are used in clinical protocols to generate modified T‐lymphocytes that target cancer cells. New designs of lentiviral vectors are being developed as a toolbox for therapy by the CRISPR/Cas9 genome editing technology.