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.

  • Short Communication
  • Published:

Restricted tissue tropism and acquired resistance to Sindbis viral vector expression in the absence of innate and adaptive immunity

Gene Therapy volume 14, pages 1166–1174 (2007)Cite this article

Abstract

Our previous studies suggest that replication-defective Sindbis vectors might be promising agents for specific tumor targeting and detection. However, the effects of innate and/or adaptive anti-viral immunity, in particular, the IFN-I/STAT1 signaling pathway, may impact their therapeutic potential. Using a bioluminescent imaging system, we demonstrate that although most normal cells are not permissively transduced by replication-defective Sindbis vector, transduction of liver non-sinusoidal endothelial occurs the first time IFN-I/STAT1 signaling deficient mice are inoculated with the vector. Transduction of some cells is not surprising since STAT1 knockout animals show significant delay in IFN responses such as the production of IFN-α/β and transcriptional activation of several anti-viral genes (IRF7, RIG-I, PKR, TLR3, USP18, ISG15). However, beyond the initial vector transduction, which resolves rapidly, secondary inoculums of Sindbis vectors do not transduce any liver cells, suggesting that an alternative antiviral pathway may protect against further transduction. Other known signaling pathways were examined using mice lacking functional TLR3, tumor necrosis factorαR or nuclear factor-kappa B (p50). Surprisingly, none of those pathways seem to play a significant role in anti-Sindbis responses. Thus it appears that in vivo, in contrast to the ready transduction of tumor cells, transduction of normal cells by replication-defective Sindbis vector is limited, possibly by a novel mechanism.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3a
Figure 3b

Similar content being viewed by others

References

  1. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003; 302: 415–419.

    Article  CAS  PubMed  Google Scholar 

  2. Tseng JC, Hurtado A, Yee H, Levin B, Boivin C, Benet M et al. Using sindbis viral vectors for specific detection and suppression of advanced ovarian cancer in animal models. Cancer Res 2004; 64: 6684–6692.

    Article  CAS  PubMed  Google Scholar 

  3. Tseng JC, Zanzonico PB, Levin B, Finn R, Larson SM, Meruelo D . Tumor-specific in vivo transfection with HSV-1 thymidine kinase gene using a Sindbis viral vector as a basis for prodrug ganciclovir activation and PET. J Nucl Med 2006; 47: 1136–1143.

    CAS  PubMed  Google Scholar 

  4. Kurkela S, Manni T, Myllynen J, Vaheri A, Vapalahti O . Clinical and laboratory manifestations of Sindbis virus infection: prospective study, Finland, 2002–2003. J Infect Dis 2005; 191: 1820–1829.

    Article  PubMed  Google Scholar 

  5. Strauss JH, Wang KS, Schmaljohn AL, Kuhn RJ, Strauss EG . Host-cell receptors for Sindbis virus. Arch Virol Suppl 1994; 9: 473–484.

    CAS  PubMed  Google Scholar 

  6. Wang KS, Kuhn RJ, Strauss EG, Ou S, Strauss JH . High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells. J Virol 1992; 66: 4992–5001.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Menard S, Tagliabue E, Colnaghi MI . The 67 kDa laminin receptor as a prognostic factor in human cancer. Breast Cancer Res Treat 1998; 52: 137–145.

    Article  CAS  PubMed  Google Scholar 

  8. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA . Molecular aspects of tumor cell invasion and metastasis. Cancer 1993; 71: 1368–1383.

    Article  CAS  PubMed  Google Scholar 

  9. Liotta LA . Tumor invasion and metastases – role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 1986; 46: 1–7.

    Article  CAS  PubMed  Google Scholar 

  10. Tseng JC, Levin B, Hirano T, Yee H, Pampeno C, Meruelo D . In vivo antitumor activity of Sindbis viral vectors. J Natl Cancer Inst 2002; 94: 1790–1802.

    Article  CAS  PubMed  Google Scholar 

  11. Tseng JC, Levin B, Hurtado A, Yee H, Perez de Castro I, Jimenez M et al. Systemic tumor targeting and killing by Sindbis viral vectors. Nat Biotechnol 2004; 22: 70–77.

    Article  CAS  PubMed  Google Scholar 

  12. Jan JT, Griffin DE . Induction of apoptosis by Sindbis virus occurs at cell entry and does not require virus replication. J Virol 1999; 73: 10296–10302.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Levine B, Huang Q, Isaacs JT, Reed JC, Griffin DE, Hardwick JM . Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene. Nature 1993; 361: 739–742.

    Article  CAS  PubMed  Google Scholar 

  14. Bredenbeek PJ, Frolov I, Rice CM, Schlesinger S . Sindbis virus expression vectors: packaging of RNA replicons by using defective helper RNAs. J Virol 1993; 67: 6439–6446.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Levy DE, Garcia-Sastre A . The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. Cytokine Growth Factor Rev 2001; 12: 143–156.

    Article  CAS  PubMed  Google Scholar 

  16. Ryman KD, Klimstra WB, Nguyen KB, Biron CA, Johnston RE . Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism. J Virol 2000; 74: 3366–3378.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Shresta S, Sharar KL, Prigozhin DM, Snider HM, Beatty PR, Harris E . Critical roles for both STAT1-dependent and STAT1-independent pathways in the control of primary dengue virus infection in mice. J Immunol 2005; 175: 3946–3954.

    Article  CAS  PubMed  Google Scholar 

  18. Byrnes AP, Griffin DE . Binding of Sindbis virus to cell surface heparan sulfate. J Virol 1998; 72: 7349–7356.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Klimstra WB, Ryman KD, Johnston RE . Adaptation of Sindbis virus to BHK cells selects for use of heparan sulfate as an attachment receptor. J Virol 1998; 72: 7357–7366.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Prakash A, Smith E, Lee CK, Levy DE . Tissue-specific positive feedback requirements for production of type I interferon following virus infection. J Biol Chem 2005; 280: 18651–18657.

    Article  CAS  PubMed  Google Scholar 

  21. Gorchakov R, Frolova E, Williams BR, Rice CM, Frolov I . PKR-dependent and -independent mechanisms are involved in translational shutoff during Sindbis virus infection. J Virol 2004; 78: 8455–8467.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D, Sonenberg N et al. Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J 2006; 25: 1730–1740.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Paladino P, Cummings DT, Noyce RS, Mossman KL . The IFN-independent response to virus particle entry provides a first line of antiviral defense that is independent of TLRs and retinoic acid-inducible gene I. J Immunol 2006; 177: 8008–8016.

    Article  CAS  PubMed  Google Scholar 

  24. Bello MJ, de Campos JM, Kusak ME, Vaquero J, Sarasa JL, Pestana A et al. Molecular analysis of genomic abnormalities in human gliomas. Cancer Genet Cytogenet 1994; 73: 122–129.

    Article  CAS  PubMed  Google Scholar 

  25. Linge C, Gewert D, Rossmann C, Bishop JA, Crowe JS . Interferon system defects in human malignant melanoma. Cancer Res 1995; 55: 4099–4104.

    CAS  PubMed  Google Scholar 

  26. Lu R, Au WC, Yeow WS, Hageman N, Pitha PM . Regulation of the promoter activity of interferon regulatory factor-7 gene. Activation by interferon snd silencing by hypermethylation. J Biol Chem 2000; 275: 31805–31812.

    Article  CAS  PubMed  Google Scholar 

  27. Sun WH, Pabon C, Alsayed Y, Huang PP, Jandeska S, Uddin S et al. Interferon-alpha resistance in a cutaneous T-cell lymphoma cell line is associated with lack of STAT1 expression. Blood 1998; 91: 570–576.

    CAS  PubMed  Google Scholar 

  28. Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND et al. Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma. J Biol Chem 1997; 272: 28779–28785.

    Article  CAS  PubMed  Google Scholar 

  29. Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 2000; 6: 821–825.

    Article  CAS  PubMed  Google Scholar 

  30. Stojdl DF, Lichty BD, tenOever BR, Paterson JM, Power AT, Knowles S et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 2003; 4: 263–275.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Christine Pampeno for critical reading of this manuscript and helpful discussions. This study was supported by US Public Health Service grants CA100687, and CA68498 from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services and Northeast Biodefense Center U54-AI057158-Lipkin, and AI28900 from NIAID.

Author information

Authors and Affiliations

  1. Department of Pathology and the NYU Gene Therapy Center, NYU Cancer Institute, NYU School of Medicine, New York University, New York, NY, USA

    J-C Tseng, Y Zheng, H Yee, D E Levy & D Meruelo

Authors
  1. J-C Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Yee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D E Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Meruelo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Meruelo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tseng, JC., Zheng, Y., Yee, H. et al. Restricted tissue tropism and acquired resistance to Sindbis viral vector expression in the absence of innate and adaptive immunity. Gene Ther 14, 1166–1174 (2007). https://doi.org/10.1038/sj.gt.3302973

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302973

Keywords

This article is cited by

Search

Advanced search

Quick links