Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Emerman, M. From curse to cure: HIV for gene therapy? Nature Biotechnol. 14, 943 (1996).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. Pedersen, N.C. The feline immunodeficiency virus, in The Retroviridae (ed at l. Levy, J.A.) 181–228 (Plenum Press, New York, 1993).

    Chapter  Google Scholar 

  5. Elder, J.H. & Phillips, T.R. Molecular properties of feline immunodeficiency virus (FIV). Infect. Agents Disease 2, 361–374 (1993).

    CAS  Google Scholar 

  6. Talbott, R.L. et al. Nucleotide sequence and genomic organization of feline immunodeficiency virus. Proc. Natl. Acad. Sci. USA 86, 5743–5747 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Olmsted, R.A. et al. Worldwide prevalence of lentivirus infection in wild feline species: Epidemiologic and phylogenetic aspects. J. Virol. 66, 6008–6018 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Baba, T.W. et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267, 1820–1825 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0398-354

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing