Immunological Insights and Translational Advances in HSV-2 Infection and Vaccine Development

Abstract

Herpes simplex virus type 2 (HSV-2) is a globally prevalent sexually transmitted infection, affecting an estimated 491 million people worldwide. The virus establishes lifelong latency in the sensory nervous system, particularly the sacral dorsal root ganglia, and periodically reactivates to cause recurrent genital lesions, asymptomatic viral shedding, and considerable psychological distress. HSV-2 infection also facilitates HIV acquisition by disrupting mucosal barriers and enhancing the recruitment of HIV target cells, contributing significantly to the global HIV burden. Despite the widespread use of antiviral agents such as acyclovir and valacyclovir, current therapies only manage symptoms and reduce shedding without eliminating the latent viral reservoir. Although numerous vaccine candidates—including subunit, viral vector, and mRNA-based platforms—have shown promise in animal studies, they have failed to demonstrate consistent and durable protection in human trials. This review synthesizes current knowledge on HSV-2 immunobiology, including the roles of innate immunity, adaptive T cell responses, and tissue-resident memory T cells in controlling viral infection. It also highlights the challenges posed by viral immune evasion strategies and evaluates emerging approaches such as CRISPR/Cas9 gene editing, latency-reversing agents, and T cell receptor (TCR) profiling. A deeper understanding of these mechanisms is essential for the development of effective, long-lasting HSV-2 interventions.