Activation of AIM2 by hepatitis B virus results in antiviral immunity that suppresses hepatitis C virus during coinfection.

Hepatitis B virus (HBV) infection in immunocompetent adults is mostly self-limiting, whereas Hepatitis C virus (HCV) infection more often becomes chronic, suggesting that HBV is more susceptible to the host immune response. It is unclear how HBV induces effective antiviral immunity, but HBV also causes anti-HCV immunity leading to lower HCV viral loads in co-infected patients. Here, we found that a pathway in which HBV dsDNA is sensed by the inflammasome protein absent in melanoma-2, leading to caspase-1 activation in monocytes, cleavage of pro-IL-18 and secretion of IL-18 protein, activation of NK cells, and their synthesis of interferon-γ. Such activation could suppress not only HBV but also HCV replication, suggesting a mechanism through which the two viruses could engage in cross-talk during coinfection. IMPORTANCE Clinical data suggest that Hepatitis C virus (HCV) levels are generally lower in Hepatitis B virus (HBV) co-infected patients, but the mechanism is unknown. Here, we show that HBV, but not HCV, activated absent in melanoma-2. This in turn results in inflammasome-mediated cleavage of pro-IL-18, leading to an innate immune activation cascade that results in increased interferon-γ, suppressing both viruses.