Restoring T cell function to promote resolution of chronic HBV infection

Abstract

Abstract An estimated 296 million people worldwide suffer from chronic hepatitis B virus (HBV) infection, with 1.5 million new infections occurring each year despite the availability of an effective vaccine. Chronic HBV infection persists in a dysfunctional immune environment, manifested by an ineffective T cell response to the virus. Patient HBV-specific CD8 +T cells have diminished proliferative capacity and cytokine production, and they exhibit increased and sustained expression of inhibitory immune checkpoint receptors. In mice with persistent HBV replication, reduction of viral antigens can be achieved by therapeutic immunization with alphavirus- and vesiculovirus-based vaccine platforms expressing HBV antigens. However, blocking PD-1 and CTLA-4 signaling may further enhance antiviral effector T cell function and therapeutic efficacy. Using a mouse model of HBV replication in which mice are transduced with adeno-associated virus encoding the HBV genome (AAV-HBV), we investigated the role of these inhibitory receptors in the T cell response to HBV. Antibody-mediated blockade of either PD-1 or CTLA-4 independently in AAV-HBV mice did not promote viral clearance. Likewise, PD-1 and CTLA-4 inhibition combined with therapeutic immunization with VSV expressing an HBV antigen did not improve anti-HBV T cell responses or virus clearance in high-antigen mice with persistent viral replication. However, in mice with lower initial antigen loads, blockade of these receptors along with VSV therapeutic immunization resulted in an enhanced decrease of circulating HBV antigen. These results suggest new methodologies for improving HBV-specific immune responses to promote a functional cure of the infection. Supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers R01AI148354 and R44DK113858. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.