Persistent LCMV Infection Is Controlled by Blockade of Type I Interferon Signaling
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.
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Published In
Science
Volume 340 | Issue 6129
12 April 2013
12 April 2013
Copyright
Copyright © 2013, American Association for the Advancement of Science.
Submission history
Received: 15 January 2013
Accepted: 28 February 2013
Published in print: 12 April 2013
Acknowledgments
The authors thank D. Fremgen, C. Cubitt, N. Ngo, and S. Rice for technical excellence. Data reported in the manuscript are tabulated in the main paper and in the supplementary materials. This research was supported by NIH grant AI09484 (M.B.A.O.); National Cancer Institute grants NCI CA43059 (R.D.S.) and U54AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE) (R.D.S. and M.B.A.O.); grants AI077719 and AI047140 (J.C.d.l.T.), postdoctoral training grants AI007354; and American Heart fellowships 11POST7430106 (J.R.T.), HL007195 (C.N.), and NS041219 (B.M.S.).
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