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Subversion of the innate immune system by a retrovirus

Nature Immunology volume 4, pages 573–578 (2003)Cite this article

Abstract

Retroviruses evolve rapidly to avoid the immune response of the infected host. We show here that the wild-type mouse mammary tumor virus MMTV(C3H) persisted indefinitely in C3H/HeN mice. However, it was rapidly lost in mice of the closely related C3H/HeJ strain and was replaced by a virus recombinant with an endogenous Mtv provirus. Maintenance of the wild-type virus was dependent on Toll-like receptor-4 (TLR4) signaling, which triggered production of the immunosuppressive cytokine interleukin-10. In the presence of mutant TLR4 in C3H/HeJ mice, wild-type virus was eliminated by the cytotoxic immune response, promoting selection of the immune escape recombinant MMTV variants. Thus, subversion of the innate immune system is yet another survival strategy used by retroviruses.

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Figure 1: Wild-type MMTV(C3H) is under selective pressure in C3H/HeJ mice and is gradually replaced with recombinant MMTV(HeJ)-like virus.
Figure 2: Newly selected MMTV is a recombinant between wild-type MMTV(C3H) and endogenous Mtv1.
Figure 3: Loss of TLR4 function results in selection of the recombinant virus.
Figure 4: TLR4 is involved in MMTV-induced immunomodulation.
Figure 5: MMTV stimulates TLR4-dependent IL-10 production.

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Acknowledgements

Supported by US National Institutes of Health grants (to T.V.G. and The Jackson Laboratory), an award from the Hillsdale Foundation (to T.V.G.) and a grant from The Jackson Laboratory (to T.V.G.). We thank D. Roopenian and S. Ross for helpful discussions and S. Williamson for the artwork. This article is dedicated to the memory of Charles Janeway, Jr.

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Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    Brooke A Jude, Yelena Pobezinskaya, Jennifer Bishop, Susannah Parke, Alexander V Chervonsky & Tatyana V Golovkina

  2. Section of Immunobiology and HHMI, Yale University Medical School, 310 Cedar Street, New Haven, 06510, Connecticut, USA

    Ruslan M Medzhitov

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Correspondence to Tatyana V Golovkina.

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Jude, B., Pobezinskaya, Y., Bishop, J. et al. Subversion of the innate immune system by a retrovirus. Nat Immunol 4, 573–578 (2003). https://doi.org/10.1038/ni926

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