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Updated: Jun 13, 2025
Stem Cell-Derived Viral Ag-Specific T Lymphocytes Suppress HBV Replication in Mice
Published on: September 25, 2019
CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice
Jacob T Bailey1, Sophia Cangialosi1, Safiehkhatoon Moshkani1
1Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
Background & Aims:
HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication.
Methods:
Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8+ T cells were quantified in the spleen and liver at the experimental endpoint.
Results:
CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8+ T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8+ T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg).
Conclusions:
Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4+ T cell-dependent limitation on CD40-mediated antiviral efficacy.
Impact And Implications:
Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8+ T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4+ cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.
