Combined PD-1 and LAG-3 Blockade Together with HLA-A*0201 Epitopes Immunotherapy Restore the Function of CD8+ TRM Cells and Reduce UV-B Induced Recurrent Ocular Herpes in HSV-1 Infected “Humanized” HLA Transgenic Mice

Abstract

Abstract Exhaustion of herpes simplex virus type 1 (HSV-1)-specific CD8+ T cells is a notable cause that contribute to the frequency and severity of recurrent herpes. In the present study, we found that functionally exhausted HSV-specific CD8+ T cells, expressing both the programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3), two immune checkpoint receptors that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, using a novel “humanized” HLA-A*0201 transgenic mouse model of UV-B induced recurrent corneal herpetic disease, we demonstrated that SYMP mice with increased virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific tissue resident PD1+LAG-3+CD8+ TRM cells in both trigeminal ganglia (TG) and cornea. Dual blockade of both PD-1 and LAG-3 pathways restored the number and function of antiviral CD8+ TRM cells and appeared to be synergistically superior to blockade of either pathway alone. Moreover, blockade of PD-1/LAG-3 immune checkpoints in combination with therapeutic vaccination with a mixture of HLA-A*0201-restricted CD8+ T cell epitopes UL9196–204, UL25572–580, and UL44400–408, recently identified from HSV-1 proteins, significantly improved protection against UV-B induced recurrent herpes. This pre-clinical study indicate that dual blockade of Immune checkpoints combined with therapeutic vaccination with human epitopes identified from HSV-1 proteins is a promising strategy to protection against recurrent herpes in human.