Herpes simplex virus (HSV) is a highly prevalent pathogen globally, establishing lifelong infections in the majority of the world’s population. HSV-1 is traditionally associated with oral lesions, while HSV-2 is primarily linked to genital infections. Both are neurotropic viruses that establish a persistent, non-replicating state within the sensory neurons of the peripheral nervous system, a process known as latency. The virus’s ability to hide in these nerve cells makes it invisible to the immune system and impenetrable to existing drug treatments. Current standard-of-care antivirals, such as acyclovir and valacyclovir, only manage active outbreaks and reduce viral shedding but cannot eliminate the latent viral DNA.
Defining the Types of Herpes Cures
The goal of finding a definitive treatment for HSV has led researchers to define two distinct outcomes, each with its own therapeutic approach. The first is a sterilizing cure, which involves the complete and permanent eradication of all viral genetic material from the body. Achieving this means the individual would be completely free of the virus, with no chance of future outbreaks or transmission.
The second outcome is a functional cure, a more immediately achievable target that aims to permanently silence the virus without removing every trace of its DNA. Under a functional cure, the virus remains latent in the nerve cells but is permanently prevented from reactivating. This state results in no symptomatic outbreaks, no viral shedding, and no risk of transmission. Therapies targeting a functional cure focus on achieving durable control over the virus.
Research Focus: Gene Editing for Viral Eradication
Gene editing technologies represent the most advanced strategy aimed at achieving a sterilizing cure by directly targeting the latent viral DNA. The HSV genome persists in the nucleus of nerve cells as a closed loop of DNA called an episome, which is the target of molecular tools designed to physically cut and disable the viral genetic material.
One promising approach uses specialized enzymes called meganucleases, which act like ultra-precise molecular scissors. Researchers have engineered these meganucleases to recognize and cut the HSV DNA in two specific locations. This targeted double-cut severely damages the episome, preventing the virus from repairing itself and prompting the cell’s natural repair mechanisms to degrade the foreign DNA.
Delivery of these gene-editing components into the sensory neurons is accomplished using an adeno-associated virus (AAV) vector. Preclinical studies using mouse models of HSV-1 infection have demonstrated significant success, with a single treatment eliminating over 90% of the latent HSV-1 DNA from the infected ganglia.
Research Focus: Therapeutic Vaccines and Immune Control
While gene editing pursues eradication, therapeutic vaccines focus on leveraging the immune system to achieve a functional cure. These vaccines are administered to people already living with HSV to enhance their immune response against the latent virus and prevent it from reactivating.
The primary mechanism involves boosting cytotoxic T-cells, often referred to as killer T-cells, which are responsible for patrolling and destroying infected cells. A stronger T-cell response can more effectively suppress the virus during its attempts to break latency and cause an outbreak or asymptomatic shedding. This constant immune surveillance aims to maintain the virus in its dormant state indefinitely.
Various platforms are being explored for these candidates, including mRNA, subunit protein, and live-attenuated vector vaccines. Moderna’s mRNA-1608 utilizes the same technology as the COVID-19 vaccines to stimulate the T-cell response.
Clinical Development Status and Expected Timelines
The most promising cure candidates are currently navigating the rigorous multi-phase process of clinical development. Gene-editing therapies are still primarily in the preclinical stage, involving extensive testing in animal models before human trials can begin. Researchers are working closely with regulatory bodies to ensure the safety and efficacy of the viral delivery vectors and gene-editing tools.
Therapeutic vaccines and novel antivirals are further along the pipeline, with several candidates having entered human trials. Moderna’s mRNA-1608 is currently undergoing a Phase 1 study to assess its safety and ability to generate an immune response. A new class of antiviral, ABI-5366, is also in Phase 1a/1b trials and is showing promise in reducing viral shedding.
These initial studies are followed by Phase 2 trials to test efficacy and then large-scale Phase 3 trials to confirm results against a placebo. While the gene-editing cure remains a longer-term prospect, therapeutic vaccine and novel antiviral candidates could potentially reach the market sooner, offering a functional cure within the next five years if trials proceed successfully.