Apoptotic caspases suppress an MDA5-driven IFN response during productive replication of human papillomavirus type 31

Human papillomaviruses (HPVs) infect the basal proliferating cells of the stratified epithelium, but the productive phase of the life cycle (consisting of viral genome amplification, late gene expression, and virion assembly) is restricted to the highly differentiated suprabasal cells. While much is known regarding the mechanisms that HPVs use to block activation of an innate immune response in undifferentiated cells, little is known concerning how HPV prevents an interferon (IFN) response upon differentiation. Here, we demonstrate that high-risk HPVs hijack a natural function of apoptotic caspases to suppress an IFN response in differentiating epithelial cells. We show that caspase inhibition results in the secretion of type I and type III IFNs that can act in a paracrine manner to induce expression of interferon-stimulated genes (ISGs) and block productive replication of HPV31. Importantly, we demonstrate that the expression of IFNs is triggered by the melanoma differentiation-associated gene 5 (MDA5)–mitochondrial antiviral-signaling protein (MAVS)–TBK1 (TANK-binding kinase 1) pathway, signifying a response to double-stranded RNA (dsRNA). Additionally, we identify a role for MDA5 and MAVS in restricting productive viral replication during the normal HPV life cycle. This study identifies a mechanism by which HPV reprograms the cellular environment of differentiating cells through caspase activation, co-opting a nondeath function of proteins normally involved in apoptosis to block antiviral signaling and promote viral replication.