Engineering HSV-1 for Gene Therapy, Oncolytic Immunotherapy, and Neuroscience.
Herpes simplex virus type 1 (HSV-1) has emerged as a versatile platform for gene delivery, oncolytic immunotherapy, and neural circuit mapping. Its large genome, broad tropism, and engineering flexibility enable delivery of large or multi-component payloads that exceed the capacity of many conventional viral vectors. HSV-1-based vectors span a continuum of architectures, each representing a distinct design space shaped by trade-offs among replication competence, payload size, immune engagement, biosafety, and manufacturing robustness. Advances in bacterial artificial chromosome recombineering, CRISPR-based editing, and synthetic genome assembly, together with insights from structural and systemic biology, have accelerated the transition from empirical vector construction to more rational programmable genome design. These technologies enable modular control of viral entry, transcription, genome replication/maintenance, and host immune interactions. Clinical successes such as T-VEC, G47Δ, and B-VEC have validated the clinical potential of HSV-1 engineering, yet broader translation remains limited by antiviral immunity, inefficient delivery, epigenetic silencing, genome instability, and manufacturing challenges. In this review, we illustrate how HSV-1 has evolved from a naturally neurotropic virus into a versatile biomedical tool, whose therapeutic and research potential emerges from the precise matching of viral properties with disease-specific requirements, delivery contexts, and functional objectives.