Abstract
The molecular bases for species barriers to lentiviral replication are not well understood, but are of interest for explaining lentiviral pathogenesis, devising therapeutic strategies, and adapting lentiviruses to gene therapy. HIV-1 -based lentiviral vectors efficiently transduce nondividing cells1, but present complex safety concerns2. Nonprimate (ungulate or feline) lentiviruses might provide safer alternatives, but these viruses display highly restricted tropisms, and their potential for adaptation as replication-defective vectors capable of transducing human cells is unknown. Feline immunodeficiency virus (FIV) does not infect humans or other non-Felidae despite prevalent natural exposure. Although long terminal repeat (LTR)-directed FIV expression was found to be negligible in human cells, promoter substitution enabled an env-deleted, three-plasmid, human cell-FIV lentiviral vector system to express high levels of FIV proteins and FIV vectors in human cells, thus bypassing the hazards of feline vector producer cells. Pseudotyped FIV vectors efficiently transduced dividing, growth-arrested, and postmitotic human targets. The experiments delineate mechanisms involved in species-restricted replication of this lentivirus and show that human cells support both productive- and infective-phase mechanisms of the FIV life cycle needed for efficient lentiviral vector transduction. Nonprimate lentiviral vectors may offer safety advantages, and FIV vectors provide unique experimental opportunities.
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References
Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).
Emerman, M. From curse to cure: HIV for gene therapy? Nature Biotechnol. 14, 943 (1996).
Pedersen, N.C., Ho, E.W., Brown, M.L. & Yamamoto, J.K. Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science 235, 790–793 (1987).
Pedersen, N.C. The feline immunodeficiency virus, in The Retroviridae (ed at l. Levy, J.A.) 181–228 (Plenum Press, New York, 1993).
Elder, J.H. & Phillips, T.R. Molecular properties of feline immunodeficiency virus (FIV). Infect. Agents Disease 2, 361–374 (1993).
Talbott, R.L. et al. Nucleotide sequence and genomic organization of feline immunodeficiency virus. Proc. Natl. Acad. Sci. USA 86, 5743–5747 (1989).
Olmsted, R.A., Hirsch, V.M., Purcell, R.H. & Johnson, P.R. Nucleotide sequence analysis of feline immunodeficiency virus: Genome organization and relationship to other lentiviruses. Proc. Natl. Acad. Sci. USA 86, 8088–8092 (1989).
Olmsted, R.A. et al. Worldwide prevalence of lentivirus infection in wild feline species: Epidemiologic and phylogenetic aspects. J. Virol. 66, 6008–6018 (1992).
Bachmann, M.H. et al. Genetic diversity of feline immunodeficiency virus: Dual infection, recombination, and distinct evolutionary rates among envelope sequence clades. J. Virol. 71, 4241–253 (1997).
Tomonaga, K. et al. Comparison of the Rev transactivation of feline immunodeficiency virus in feline and non-feline cell lines. J. Veterinary Med. Sci. 56, 199–201 (1994).
Miyazawa, T. et al. Production of feline immunodeficiency virus in feline and non-feline non-lymphoid cell lines by transfection of an infectious molecular clone. J. Genl. Virol. 73, 1543–1546 (1992).
Sparger, E.E. et al. Regulation of gene expression directed by the long terminal repeat of the feline immunodeficiency virus. Virology 187, 165–177 (1992).
Takeuchi, Y. et al. Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell. J. Virol. 68, 8001 8007 (1994).
Remington, K.M., Chesebro, B., Wehrly, K., Pedersen, N.C. & North, T.W. Mutants of feline immunodeficiency virus resistant to 3′-azido-3′-deoxythymidine. J. Virol. 65, 308–312 (1991).
Burns, J.C., Friedmann, T., Driever, W., Burrascano, M. & Yee, J.K. Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: Concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells. Proc. Natl. Acad. Sci. USA 90, 8033–8037 (1993).
Pleasure, S.J., Page, C. & Lee, V.M. Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons. J. Neurosci. 12, 1802–1815 (1992).
Baba, T.W. et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267, 1820–1825 (1995).
Willey, R.L. et al. In vitro mutagenesis identifies a region within the envelope gene of the human immunodeficiency virus that is critical for infectivity. J. Virol. 62, 139–147 (1988).
Kornbluth, R.S., Oh, P.S., Munis, J.R., Cleveland, P.H. & Richman, D.D. Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. J. Exp. Med. 169, 1137–1151 (1989).
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Poeschla, E., Wong-Staal, F. & Looney, D. Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat Med 4, 354–357 (1998). https://doi.org/10.1038/nm0398-354
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DOI: https://doi.org/10.1038/nm0398-354
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