149135.fig.004
Figure 4: Blockade of T-cell inhibitory pathways to boost immunity to herpes simplex virus infections. Multiple inhibitory pathways may be activated in the exhausted CD8+ T cells in the HSV-1 latently infected TG, including PD-1, TIM-3, and LAG-3. Blockade of one T-cell inhibitory pathway may partially restore HSV-specific CD8+ T-cell effector functions. Blocking antibodies may be directed against the PD-1, TIM-3 and LAG-3 T-cell inhibitory receptors on CD8+ T cells or possibly their ligands (PD-L1 galectin-9 and MHC-II, resp.) on infected neurons or on DC. Full restoration of CD8+ T-cell function may require blockade of two or more inhibitory pathways or a combination of pathway blockade and vaccination. Sustained restoration of DC maturation may be also crucial for functional CD8+ T-cell function and clinical cure. HSV-1 LAT gene appears-interfering with both CD8+ T-cell function and with DC maturation. How CD8+ T cells are dysfunctional and DC are silenced, and the pathways to rescue this silencing, is still unknown.