CCR5 deficiency enhances hepatic innate immune cell recruitment & inflammation in a murine model of acute hepatitis B infection.

Human genetic studies demonstrate a link between the 32-bp deletion that produces a nonfunctional CCR5 receptor (CCR5∆32) and enhanced recovery from acute hepatitis B virus (HBV) infection. To investigate the role of CCR5 in immune responses to acute HBV, we intravenously infected Ccr5+/+ (WT) and Ccr5-/- (KO) mice with a replication-incompetent adenovirus containing the overlapping HBV1.3 construct (AdHBV), or vector control. At day 3 following AdHBV infection, analysis of intrahepatic leukocytes (IHL) showed KO mice had increased CD11b+ NK cells compared to WT (18.2% vs 7.6% of live IHL, P-value <0.01). These CD11b+ NK cells were non-resident (CD49a- ) and had capacity to degranulate and produce IFN-γ following stimulation. At day 3, plasma CXCL10 was significantly increased in KO, but not WT, mice receiving AdHBV as compared to vector control, while CXCR3 expression on hepatic CD11b+ NK cells in AdHBV-treated KO mice was significantly lower compared to uninfected mice, suggesting these NK cells are recruited along the CXCL10/CXCR3 axis. At days 7 and 14, no differences between genotypes were observed in number, or HBV-specific function, of intrahepatic CD8+ T cells. Instead, at day 14, KO mice had increased intrahepatic pro-inflammatory monocytes compared to WT mice (17.56% vs 6.57% of live IHL, p = 0.014), corresponding with an increase in plasma ALT and intrahepatic IL-1β observed in KO mice. Taken together, these findings demonstrate that loss of CCR5 signaling drives a more robust inflammatory liver microenvironment early in acute HBV infection via enrichment of hepatic innate immune cells. This article is protected by copyright. All rights reserved.