Nonprimate lentiviral vectors.

Abstract

Advances in the nascent field of gene therapy have created a demand for gene transfer vehicles that are capable of safely and stably delivering genes to both dividing and nondividing cells. Retroviral vectors, by virtue of their ability to permanently integrate genes of interest into the target cell genome, have played a prominent role in much of the gene transfer research to date. However, their inability to transduce quiescent cells has rendered them largely ineffective for clinical applications. In contrast, adenoviral vectors are capable of infecting nondividing cells, but attempts to move these vectors into the clinic have been limited at times by their lack of stable expression and high immunogenicity. Lentiviral vectors offer a unique combination of the advantages of these two systems without many of the pitfalls. Lentiviruses can stably transduce both dividing and nondividing cells, and, unlike adenoviral vectors, are not immunogenic in vivo. The most established and tested lentiviral vectors are those based on the human immunodeficiency virus (HIV-1). As a full-length virus, HIV is naturally optimized for production in and transduction of human cells and, as such, has proved an ideal candidate for development into a human gene transfer vector. Concern over the consequences of using vectors based on a pathogenic virus with such an optimized tropism for human cells has, however, limited the clinical applications of HIV vectors. For these reasons, vector development has begun to shift to other members of the lentivirus family that do not infect primates as part of their normal host range. In addition to the potential biosafety benefits, it is possible that some nonprimate lentiviral vectors will show an increased ability to infect some useful cell types relative to HIV-based vectors. As many of these viruses have not been well characterized biologically, an interesting cross-talk has developed where advances in lentiviral biology impact vector development and vice versa. The recent discovery of the central DNA flap in lentiviral genomes and its role in nuclear import of preintegration complexes, for example, may prove critical in bringing the efficiency of nonprimate lentiviral vectors up to the level of HIV vectors. As it appears that these nonprimate vectors might reach parity with their primate counterparts in terms of efficiency and tropism, it must now be considered whether they are truly safer for use in the clinic. This review will focus on those aspects of nonprimate lentiviral biology which make such vectors potentially useful in clinical settings.