Human retinoic acid-inducible gene I (RIG-I) deficiency associated with susceptibility to classic Kaposi sarcoma

Kaposi sarcoma (KS), driven by the DNA virus KS-associated herpesvirus (KSHV), arises in the context of T-cell immunosuppression (eg, human immunodeficiency virus infection, transplantation) or sporadically in ostensibly immunocompetent older adults (endemic or classic KS). The mechanisms underlying KS development without exogenous immunosuppression remain unclear. Retinoic acid-inducible gene I (RIG-I), encoded by DDX58, is a canonical cytosolic sensor of RNA viruses, but its role in human immunity to DNA viruses is not well understood.

We report a patient with RIG-I deficiency and KS and define associated antiviral and host response defects.

Whole-exome sequencing was performed to identify the genetic basis of the immunodeficiency. RIG-I-dependent antiviral signaling was evaluated through functional studies using fluorescent KSHV in patient-derived lymphoblastoid cell lines and isogenic fibroblast and endothelial models. Aberrant cellular responses during KSHV infection, latency, and reactivation in the context of RIG-I deficiency were assessed through transcriptomic, proteomic, and live-cell imaging analyses.

A homozygous nonsense DDX58 mutation (p.Q393∗) was identified in a patient with classic KS, abolishing RIG-I expression and specifically impairing responses to RIG-I agonists. Loss of RIG-I compromised type I interferon responses to both primary KSHV infection and virus reactivation, with skewing to a persistent latent viral program and dysregulating cellular pro-oncogenic pathways.

This study links RIG-I deficiency to classic KS and supports its role as a candidate inborn error of innate immunity shaping KSHV pathogenesis. The findings extend RIG-I's antiviral relevance beyond RNA viruses. Additional patients will clarify the virus susceptibility spectrum.