Early CD4⁺ T cell help prevents partial CD8⁺ T cell exhaustion and promotes maintenance of herpes simplex virus 1 latency

HSV-specific CD8⁺ T cells provide constant immunosurveillance of HSV-1 latently infected neurons in sensory ganglia, and their functional properties are influenced by the presence of latent virus. In this study, we show that ganglionic HSV-specific CD8⁺ T cells exhibit a higher functional avidity (ability to respond to low epitope density) than their counterparts in noninfected lungs, satisfying a need for memory effector cells that can respond to low densities of viral epitopes on latently infected neurons. We further show that lack of CD4⁺ T cell help during priming leads to a transient inability to control latent virus, which was associated with a PD-1/PD-L1 mediated reduced functional avidity of ganglionic HSV-specific CD8⁺ T cells. CD4⁺ T cells are not needed to maintain CD8⁺ T cell memory through 34 d after infection, nor do they have a direct involvement in the maintenance of HSV-1 latency.