New immunodeficiency syndromes that help us understand the IFN-mediated antiviral immune response.

Abstract

Studying primary immunodeficiencies (PIDs) provides insights into human antiviral immunity in the natural infectious environment. This review describes new PIDs with genetic defects that impair innate antiviral responses. New genetic defects in the interferon (IFN) signaling pathway include IFNAR1 deficiency, which causes uncontrolled infections with measles-mumps-rubella or yellow fever vaccines, and possibly also cytomegalovirus (CMV); and IRF9 deficiency, which results in influenza virus susceptibility. Genetic defects in several pattern recognition receptors include MDA5 deficiency, which impairs viral RNA sensing and confers human rhinovirus susceptibility; RNA polymerase III haploinsufficiency, which impairs sensing of A:T-rich virus DNA and confers VZV susceptibility; and TLR3 deficiency, which causes HSV-1 encephalitis (HSE) or influenza virus pneumonitis. Defects in RNA metabolism, such as that caused by Debranching enzyme 1 deficiency, can cause virus meningoencephalitis. Finally, defects in host restriction factors for virus replication, such as in CIB1 deficiency, contribute to uncontrolled β-HPV infections. Several new PIDs highlight the role of type I/III IFN signaling pathway, virus sensors, and host virus restriction factors in human antiviral immunity.