Non-cytotoxic antiviral activities of granzymes in the context of the immune antiviral state

Viruses are obligatory intracellular parasites, whose replication depends on components encoded by the virus and pathways and functions of the host cell. In addition to the pathways required for viral synthesis, viruses activate multiple mechanisms to evade immune attack, promoting viral propagation while avoiding or slowing the host immune response. To achieve efficient control of viral infections, the immune system in vertebrates relies on diverse and synergistic antiviral pathways (both at the innate and adaptive immune response), which target and inactivate viral and host components involved both in viral replication and in viral defenses that block host antiviral activities. During this process, the immune system uses mechanisms to slow down viral propagation, while apoptotic pathways are triggered to kill (when possible) the infected cell. Granzymes (granule enzymes) are key components of the immune response that play important roles in eliminating host cells infected by intracellular pathogens. Although the induction of target cell death has been considered the central function for these proteases, recent evidence supports that granzymes can achieve direct antiviral activities through the cleavage of viral and host factors required for viral replication and viral defense. In addition, granzyme A can stimulate the production of pro-inflammatory cytokines. The focus of this review is to discuss recent views on antiviral mechanisms involved in controlling viral infections, with special interest in novel and potential non-death-related antiviral functions of the granzymes, and how these unique functions complement and synergize with the 'antiviral state' created by interferons and cytotoxic lymphocytes in response to virus.