CD40-dependent mechanism of virus control in a mouse model of HBV infection

Abstract

Abstract An estimated 296 million people worldwide currently live with chronic hepatitis B virus (HBV) infection. Up to 90% of newborns and 30% of children with acute hepatitis B develop chronic infections, causing lifelong complications including liver cirrhosis and cancer. HBV persistence is a consequence of T and B cell dysfunction, so immunotherapy has been proposed as a means of HBV control. TNF receptor superfamily member CD40 has shown therapeutic value in overriding T cell exhaustion and inducing lymphocyte responses in solid tumors and viral infections. To determine the efficacy of CD40 targeting in generating HBV-resolving immune responses, mice were simultaneously transduced with adeno-associated virus encoding the HBV genome (AAV-HBV) and treated with the agonistic CD40 antibody FGK4.5 to activate CD40 signaling. AAV-HBV mice receiving FGK4.5 saw a transient reduction in HBV as determined by serum antigen analysis, while antigen levels in CD4-depleted mice treated with FGK4.5 became undetectable over seven weeks. HBV control was strongly associated with the generation of HBV-specific CD8 +T cells, increased serum ALT, and elevated expression of intrahepatic CD8 +T cell-related genes. Histological analysis of the liver revealed loss of hepatitis B core antigen-positive hepatocytes and increased inflammatory foci. Neither Treg cell depletion nor checkpoint inhibition in CD4-replete mice affected HBV control. Lastly, CD40 activation in CD4-depleted chronically infected mice also reduced both serum antigenemia and liver HBV RNA. Taken together, these results implicate a critical role of CD4 +T cells in maintaining HBV immune tolerance and further suggest CD40 as a potential therapeutic target for chronic HBV infection. Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI124006 and R01AI148354. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.