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RNase H-mediated retrovirus destruction in vivo triggered by oligodeoxynucleotides

Nature Biotechnology volume 25, pages 669–674 (2007)Cite this article

Abstract

The HIV-1 RNase H can be prematurely activated by oligodeoxynucleotides targeting the highly conserved polypurine tract required for second strand DNA synthesis1,2,3,4,5. This inhibits retroviral replication in cell-free HIV particles and newly infected cells1,2,3,4. Here we extend these studies to an in vivo model of retroviral replication. Mice that are chronically infected with the spleen focus-forming virus and treated with oligodeoxynucleotides that target the polypurine tract, exhibit either transient or long-term reductions in plasma virus titer, depending on the therapeutic regimen. Treatment prior to, during or shortly after infection can delay disease progression, increase survival rates and prevent viral infection. This strategy destroys viral RNA template in virus particles in serum as well as early retroviral replication intermediates in infected cells. As it targets events common to the replication cycle of all retroviruses, this approach may be broadly applicable to retroviruses of medical and agricultural importance.

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Figure 1: Oligonucleotides and RT/RNase H.
Figure 2: Effects of ODNs on SFFV virions and SFFV-infected cells.
Figure 3: Effect of ODN treatment after 5-d-SFFV infection of Swiss mice.
Figure 4: Abrogation of SFFV infectivity by early treatment with ODNs in mice.

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Acknowledgements

This work was in part supported by the J.B. Pendleton Charitable Trust for some animal studies with SCID mice, which we gratefully acknowledge. Some preliminary animal studies were performed by E. Operschall. We are grateful to J. Pavlovic for support of the project and for help with the animal work. We gratefully acknowledge the excellent technical assistance of Susanne Dettwiler. The animal care of P. Burger and S. Ressegatti is gratefully acknowledged. We thank E. LeClerq, Brussels, and B.A. Beutler, La Jolla, California, USA, for performing the AZT and TLR9 studies, and R. Weiss, London, for helpful discussion. We thank S. Mathur for sequencing of SFFV before and after passage.

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Author notes

  1. Kathrin Matzen & Anja Nitzsche

    Present address: Present addresses: Karlstrasse 41, 80333 Munich, Germany (K.M.) and Elswigstrasse 68, 23562 Lubeck, Germany (A.N.).,

  2. Kathrin Matzen, Lina Elzaouk and Alexey A Matskevich: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Virology, University of Zurich, Gloriastrasse 30, Zurich, 8006, Switzerland

    Kathrin Matzen, Lina Elzaouk, Alexey A Matskevich, Jochen Heinrich & Karin Moelling

Authors
  1. Kathrin Matzen
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  2. Lina Elzaouk
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  4. Anja Nitzsche
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  6. Karin Moelling
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Contributions

K.Matzen: animal studies; L.E.: animal studies; A.A.M. and A.N.: SFFV cell culture and in vitro studies; J.H.: in vitro studies, cleavages assays, arrangement of figures; K. Moelling: initiation and design of project, establishment of SFFV model, animal studies, writing of the manuscript.

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Correspondence to Karin Moelling.

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Matzen, K., Elzaouk, L., Matskevich, A. et al. RNase H-mediated retrovirus destruction in vivo triggered by oligodeoxynucleotides. Nat Biotechnol 25, 669–674 (2007). https://doi.org/10.1038/nbt1311

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