Therapeutic Prime/Pull Vaccination of HSV-2 Infected Guinea Pigs with the Ribonucleotide Reductase 2 (RR2) Protein and CXCL11 Chemokine Boosts Antiviral Local Tissue-Resident and Effector Memory CD4⁺ and CD8⁺ T Cells and Protects Against Recurrent Genital Herpes

Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes latency in sensory neurons of the dorsal root ganglia (DRG). Intermittent virus reactivation from latency and shedding in the vaginal mucosa (VM) causes recurrent genital herpes. While T-cells appear to play a role in controlling virus reactivation and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T-cells into DRG and VM tissues remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4⁺ and CD8⁺ T cells and its effect on the frequency and severity of recurrent genital herpes. HSV-2 latent-infected guinea pigs were immunized intramuscularly with the HSV-1 RR2 protein (Prime) and subsequently treated intravaginally with the neurotropic adeno-associated virus type 8 (AAV-8) expressing CXCL9, CXCL10, or CXCL11 T-cell-attracting chemokines (Pull). Compared to the RR2 therapeutic vaccine alone, the RR2/CXCL11 prime/pull therapeutic vaccine significantly increased the frequencies of functional tissue-resident (T_RM cells) and effector (T_EM cells) memory CD4⁺ and CD8⁺ T cells in both DRG and VM tissues. This was associated with less virus shedding in the healed genital mucosal epithelium and reduced frequency and severity of recurrent genital herpes. These findings confirm the role of local DRG- and VM-resident CD4⁺ and CD8⁺ T_RM and T_EM cells in reducing virus reactivation shedding and the severity of recurrent genital herpes and propose the novel prime/pull vaccine strategy to protect against recurrent genital herpes.