Interfering too soon: Type I interferons can dampen antiviral immunity

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Science Translational Medicine  09 Sep 2020:
Vol. 12, Issue 560, eabe1706
DOI: 10.1126/scitranslmed.abe1706


Short-term blockade of type I interferons at the time of viral infection or vaccine administration enhances immunological memory.

During viral infection, type I interferons (IFN-I) are secreted to provide immediate antiviral innate immunity in part by promoting antigen presentation and activating the adaptive immune system. Immunology dogma states that a strong innate immune response begets a strong adaptive immune response. Still, is it possible that efficient control of viral replication by IFN-I signaling results in less antigen and is actually counterproductive for building immunological memory?

Palacio and colleagues investigated this question by inoculating mice with a variety of different viruses and simultaneously coadministering a one-time dose of an antibody that blocks the IFN-I receptor. This transient IFN-I blockade resulted in a brief spike in viral antigen, although amounts of circulating virus remained low and all mice cleared infection within a week. However, the abundance of viral antigen during this early phase of the adaptive immune response resulted in a more vigorous antiviral response, as demonstrated by higher numbers of circulating virus-specific effector memory cytotoxic T cells and more virus-specific antibody production. This correlated with enhanced host protection upon rechallenge with the same virus and cross-protection against different viral strains. The adjuvant effects of transient IFN-I blockade were observed only for viruses capable of infecting additional cells during the brief blockade. Once the blockade remitted, the consequent increase in viral load caused a surge in IFN-I levels, triggering dendritic cells to provide more effective stimulation of the adaptive immune system. Excitingly, Palacio and colleagues demonstrated that this immunostimulatory phenomenon extends to viral vaccines: transient IFN-I blockade in mice also improved vaccine immunogenicity and, in the case of an experimental Human Immunodeficiency Virus (HIV)-1 vaccine, enabled better recognition of a different strain of HIV.

The work of Palacio and colleagues is timely. Rational vaccine design is more pressing now during the COVID-19 pandemic than ever before. Additionally, IFN-I signaling has come under scrutiny for its role in aggravating disease in patients with COVID-19, with dozens of studies examining a role for IFN-I signaling blockade in progress. Perhaps beyond attenuating excessive damage caused by the immune response, early blockade of IFN-I could promote durable immunity against many types of viral infections.

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