Gene therapy of HIV-1 infection using lentiviral vectors expressing anti-HIV-1 genes

Abstract

The use of vectors based on primate lentiviruses for gene therapy of human immunodeficiency virus type 1 (HIV-1) infection has many potential advantages over the previous murine retroviral vectors used for delivery of genes that inhibit replication of HIV-1. First, lentiviral vectors have the ability to transduce dividing and nondividing cells that constitute the targets of HIV-1 infection such as resting T cells, dendritic cells, and macrophages. Lentiviral vectors can also transfer genes to hematopoietic stem cells with a superior gene transfer efficiency and without affecting the repopulating capacity of these cells. Second, these vectors could be potentially mobilized in vivo by the wild-type virus to secondary target cells, thus expanding the protection to previously untransduced cells. And finally, lentiviral vector backbones have the ability to block HIV-1 replication by several mechanisms that include sequestration of the regulatory proteins Tat and Rev, competition for packaging into virions, and by inhibition of reverse transcription in heterodimeric virions with possible generation of nonfunctional recombinants between the vector and viral genomes. The inhibitory ability of lentiviral vectors can be further increased by expression of anti-HIV-1 genes. In this case, the lentiviral vector packaging system has to be modified to become resistant to the anti-HIV-1 genes expressed by the vector in order to avoid self-inhibition of the vector packaging system during vector production. This review focuses on the use of lentiviral vectors as the main agents to mediate inhibition of HIV-1 replication and discusses the different genetic intervention strategies for gene therapy of HIV-1 infection.