Targeting Herpesvirus Recombination Proteins for Antiviral Therapy

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) remain among the most prevalent human pathogens, imposing a substantial global health burden. Recurrent orolabial and genital lesions affect millions worldwide, reflecting lifelong infection and the limited ability of current therapies to prevent reactivation and transmission. There have been no major therapeutic advances in over 40 years, and an effective vaccine remains elusive. New antivirals with novel mechanisms are needed, both to combat resistant strains and to enable combination therapies that reduce toxicity and potentially limit persistence. Recombination is a universal process essential for DNA replication, repair, and genome diversification. Increasing evidence indicates that HSV replication involves single-strand annealing (SSA) mediated by a conserved two-component recombination system composed of UL12, a 5'→3' exonuclease, and ICP8, the viral SSAP (single-strand annealing protein). Both UL12 nuclease activity and ICP8 DNA binding and annealing functions are required for productive infection, identifying them as promising targets for broad-spectrum antiviral development across human herpesviruses.