Concerted synergy between viral-specific IgG and CD8+ T cells is critical for clearance of an HCV-related rodent hepacivirus

Abstract

Evidence assessing the role of B cells and their antibodies, or lack thereof, in the spontaneous resolution of hepatitis C virus (HCV) infection is conflicting. Utilization of a strictly hepatotropic, HCV-related rodent hepacivirus (RHV) circumvents many of the challenges facing the field in characterizing the immunological correlates of dichotomous infection outcomes. While WT mice clear this infection within ~4 weeks, select immunological perturbations can induce infection persisting for the lifetime of the mice, like chronic HCV infection in humans. As such, µMT mice, congenitally lacking mature B cells, were found to develop chronic RHV infection. After identifying their defective antiviral Th1 responses, the direct B cell-dependent nature of RHV clearance was confirmed by the persistent infection of WT mice depleted of B cells despite mounting fully functional T cell responses. The persistent infection developed by B1-8i and AIDcre/cre mice revealed that antigen-specific, class-switched B cells or their antibodies were crucial for viral resolution. Passive transfer of IgG purified from RHV- or LCMV-cleared donors into AIDcre/cre recipients led to clearance only in αRHV IgG recipients. Further, transfer of αRHV IgG into B cell depleted recipients also induced viral resolution. This ability of RHV-specific IgG to induce viral clearance was found to require the concomitant presence of CD8+ T cells. Due to the concerted synergy employed by these immunoglobulins and the T cell compartment in driving RHV resolution, HCV vaccine regimens should aim to simultaneously elicit robust HCV-specific antibody and T cell responses for optimal protective efficacy.