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Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling

Science, 12 April 2013
Vol. 340, Issue 6129, p. 207-211
DOI: 10.1126/science.1235214

Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling

  1. John R. Teijaro1,*,
  2. Cherie Ng1,*,
  3. Andrew M. Lee1,,
  4. Brian M. Sullivan1,
  5. Kathleen C. F. Sheehan2,
  6. Megan Welch1,
  7. Robert D. Schreiber2,
  8. Juan Carlos de la Torre1,
  9. Michael B. A. Oldstone1,
  1. 1Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
  2. 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  1. Corresponding author. E-mail: mbaobo{at}scripps.edu
  1. * These authors contributed equally to this work.

  • Present address: Center for Genetics of Host Defense, Immunology, University of Texas Southwestern, Dallas, TX 75390–8505, USA.

INTERFER(ON)ing Persistence

During persistent viral infections, a dysregulated immune response fails to control the infection. Wilson et al. (p. 202) and Teijaro et al. (p. 207; see the Perspective by Odorizzi and Wherry) show this occurs because type I interferons (IFN I), critical for early responses to viral infection, contribute to the altered immunity seen during persistent infection. Antibody blockade of IFN I signaling during chronic lymphocytic choriomeningitis virus (LCMV) in mice resulted in reduced viral titers at later stages of infection, reduced expression of inhibitory immune molecules and prevented the disruptions to secondary lymphoid organs typically observed during persistent infection with LCMV. Whether type I IFNs are also detrimental to persistent viral infection humans, such as HIV and hepatitis C virus, remains to be determined.

Abstract

During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell–dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections.

  • Received for publication 15 January 2013.
  • Accepted for publication 28 February 2013.

Citation:

J. R. Teijaro, C. Ng, A. M. Lee, B. M. Sullivan, K. C. Sheehan, M. Welch, R. D. Schreiber, J. Carlos de la Torre, and M. B. Oldstone, Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling. Science 340, 207-211 (2013).

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