Local CD4 and CD8 T-Cell Reactivity to HSV-1 Antigens Documents Broad Viral Protein Expression and Immune Competence in Latently Infected Human Trigeminal Ganglia

Herpes simplex virus type 1 (hsv-1) infection results in lifelong chronic infection of trigeminal ganglion (tg) neurons,also referred to as neuronal hsv-1 latency,with periodic reactivation leading to recrudescent herpetic disease in some persons. hsv-1 proteins are expressed in a temporally coordinated fashion during lytic infection,but their expression pattern during latent infection is largely unknown. selective retention of hsv-1 reactive t-cells in human tg suggests their role in controlling reactivation by recognizing locally expressed hsv-1 proteins. we characterized the hsv-1 proteins recognized by virus-specific cd4 and cd8 t-cells recovered from human hsv-1-infected tg. t-cell clusters,consisting of both cd4 and cd8 t-cells,surrounded neurons and expressed mrnas and proteins consistent with in situ antigen recognition and antiviral function. hsv-1 proteome-wide scans revealed that intra-tg t-cell responses included both cd4 and cd8 t-cells directed to one to three hsv-1 proteins per person. hsv-1 protein icp6 was targeted by cd8 t-cells in 4 of 8 hla-discordant donors. in situ tetramer staining demonstrated hsv-1-specific cd8 t-cells juxtaposed to tg neurons. intra-tg retention of virus-specific cd4 t-cells,validated to the hsv-1 peptide level,implies trafficking of viral proteins from neurons to hla class ii-expressing non-neuronal cells for antigen presentation. the diversity of viral proteins targeted by tg t-cells across all kinetic and functional classes of viral proteins suggests broad hsv-1 protein expression,and viral antigen processing and presentation,in latently infected human tg. collectively,the human tg represents an immunocompetent environment for both cd4 and cd8 t-cell recognition of hsv-1 proteins expressed during latent infection. hsv-1 proteins recognized by tg-resident t-cells,particularly icp6 and vp16,are potential hsv-1 vaccine candidates. © 2013 van velzen et al.