The Herpes Simplex Virus (HSV) affects billions of people globally. An estimated 64% of the global population under the age of 50 carries HSV-1, the primary cause of oral herpes, while about 13% of people aged 15–49 are infected with HSV-2, the main cause of genital herpes. Current treatments rely on suppressive antiviral medications that manage symptoms and reduce the frequency of outbreaks but do not eliminate the virus. The persistent nature of the infection is driving a focused scientific effort to develop a definitive cure.
The Biological Obstacle to Eradicating Herpes
The primary challenge in curing herpes stems from the virus’s ability to enter a dormant state known as latency. After the initial infection, the Herpes Simplex Virus travels along nerve pathways and settles within the sensory nerve ganglia, specifically the dorsal root ganglia (DRG). The virus’s genetic material hides inside the nucleus of these nerve cells, where it remains silent without actively replicating.
Current antiviral drugs, such as acyclovir and valacyclovir, are designed to interrupt the active replication process of the virus. These nucleoside analogs mimic a building block of DNA and are incorporated into the viral DNA chain, halting the virus’s ability to copy itself. Because the latent virus is not actively reproducing, these medications have no mechanism to target or destroy the dormant viral DNA within the nerve cell.
This latency allows the virus to evade both the host’s immune system and systemic drug treatments. The viral genome persists, waiting for triggers like stress or illness to reactivate. When reactivation occurs, the virus travels back down the nerve to the skin or mucosal surface, causing the symptomatic outbreaks that characterize the infection.
Cutting-Edge Strategies in Cure Research
The search for a cure has led researchers to pursue three distinct strategies to overcome the challenge of latency. These approaches focus on either physically destroying the viral DNA, training the immune system to find the infected cells, or permanently locking the virus into its dormant state.
Gene Editing and Therapy
This strategy aims for a sterilizing cure by directly removing the viral DNA from the host cell genome. Researchers at institutions like the Fred Hutch Cancer Center are developing gene-editing tools, such as meganucleases, which act like molecular scissors. These enzymes are engineered to specifically recognize and cut the HSV DNA sequence within the nerve cell nucleus.
The meganucleases are delivered to the latent neurons via an adeno-associated virus (AAV) vector. Pre-clinical studies in mouse models have demonstrated that this approach can reduce the latent viral load of HSV-1 by 90% or more. The dual cuts on the viral DNA cause such extensive damage that the cell’s repair mechanisms recognize the viral DNA as foreign and destroy it.
Therapeutic Vaccines
Unlike traditional prophylactic vaccines that aim to prevent infection, therapeutic vaccines are designed for people who are already infected with HSV. The goal is to stimulate a T-cell response to seek out and destroy cells harboring the latent virus and prevent viral shedding.
Several therapeutic vaccine candidates are currently in clinical trials, including Moderna’s mRNA-1608. These vaccines present specific viral proteins to the immune system, teaching T-cells to patrol the nerve ganglia and mucosal tissue. A stronger immune response is expected to significantly suppress viral reactivation, leading to fewer outbreaks and reduced transmission.
Latency Reversal or Blockade
This approach involves either forcing the virus out of latency or preventing it from ever reactivating. The latency reversal method uses specific drugs to “wake up” the dormant virus, forcing it to begin replication so it can be targeted and killed by existing or new antivirals.
The latency blockade strategy involves developing new classes of antivirals that target viral processes distinct from DNA replication. For example, helicase-primase inhibitors, such as pritelivir and Assembly Biosciences’ ABI-5366 (in Phase 1a/1b trials), block the virus’s ability to unwind and copy its DNA. This action prevents the virus from leaving the latent state and aims to permanently suppress reactivation.
Defining Success and Projected Timelines
The term “cure” in infectious disease research is often broken down into two distinct categories. A sterilizing cure means the complete eradication of the virus from the body, which is the ultimate goal of gene-editing approaches. A functional cure means the virus remains in the body, but it is permanently suppressed to a level where it causes no symptoms, no outbreaks, and no risk of transmission.
A functional cure is the focus of therapeutic vaccines and new-class antivirals. The time required for a functional cure to reach the market depends on the completion of clinical trials. Phase 1 trials test safety, Phase 2 tests efficacy and dosing, and Phase 3 confirms efficacy in large populations.
Therapeutic vaccine and latency blockade candidates, which are already in Phase 1 and 2 human trials, are expected to deliver the first functional cure. For example, Moderna’s mRNA-1608 Phase 1/2 trial is anticipated to conclude around 2025, and interim data for the ABI-5366 helicase-primase inhibitor are also expected in early 2025. Given the typical timeline for Phase 3 and regulatory approval, the first functional cure could potentially be available in the late 2020s. The sterilizing cure approach, represented by gene therapy, is still in the pre-clinical stage and will require a longer development period.