Persistent LCMV infection is controlled by blockade of type 1 interferon signaling

By J. Teijaro, C. Ng, A. M. Lee, B. Sullivan, K. Sheehan, M. Welch, Robert Schreiber, J. C. de la Torre, M. Oldstone. Science, 2013

783 citations recorded by the source corpus.

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. Blockade of type I interferons leads to better control of persistent lymphocytic choriomeningitis virus infection. [Also see Perspective by Odorizzi and Wherry] 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/c5e9dd48468a24e2ac9e63b304812a19d518ff2b

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Citations in the corpus

Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice (2016, positive): “Furthermore, during persistent viral infections such as those caused by lymphocytic choriomeningitis virus or SIV, IFN-I promotes chronic immune activation and upregulates the expression of inhibitory molecules such as PD-1 and LAG-3, resulting in impaired T cell responses (Sandler et al., 2014; Tei”
Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction (2013, positive): “Furthermore, suppressive cytokines such as IL-10 and transforming growth factor (TGF-β), immune cells including myeloid suppressor cells [81], Foxp3+ CD4+ regulatory T cells [7], and prolonged production of type I interferons (IFN-α/β) that paradoxically up-regulate expression and production of inhi”
Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer (2015, positive): “Other genes include interferon stimulated genes, which may promote immune suppression through PD-L1 10,11 .”
Shared and Distinct Functions of Type I and Type III Interferons (2019, neutral): “Nonetheless, the standard 48-week pegylated-IFN-a2A therapy is difficult to tolerate (Terrault et al., 2016), and treatment is contraindicated in pregnant women and in those with advanced liver disease and decompensated cirrhosis.”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Administration of anti-IFNAR1 following establishment of T cell exhaustion also enhanced viral control (183, 184), highlighting the complexity of the antiviral versus proexhaustion balance for these cytokines.”