HSV is one of the most widespread human pathogens, causing lifelong infections. Herpes Simplex Virus Type 1 (HSV-1) causes oral herpes (cold sores), while Type 2 (HSV-2) primarily causes genital herpes, though both can infect either region. Billions of people worldwide live with one or both forms of the virus. Current antiviral medications, such as acyclovir and valacyclovir, manage symptoms and reduce outbreak frequency by inhibiting viral DNA replication. However, these treatments do not eliminate the virus from the body, meaning a true cure remains elusive and research into new strategies is highly active.
Understanding Viral Latency
The primary challenge to curing herpes is the virus’s ability to establish a lifelong latent infection within the nervous system. After the initial infection, the virus travels along sensory nerves to the cell bodies of neurons, settling in the sensory nerve ganglia. HSV-1 often resides in the trigeminal ganglia, while HSV-2 typically resides in the sacral ganglia.
During this latent phase, the viral double-stranded DNA remains dormant inside the neuron’s nucleus as an episome. The virus suppresses gene expression, making it invisible to the immune system and unresponsive to traditional antiviral drugs. The virus can periodically reactivate due to triggers like stress, travel back down the nerve axons, and cause symptomatic outbreaks.
Therapeutic Vaccines and New Drug Strategies
Current research focuses on achieving a “functional cure,” aiming to reduce the frequency of viral shedding and outbreaks to near-zero levels. Therapeutic vaccines are designed to boost the body’s existing immune response to control the virus and prevent reactivation in infected individuals. Moderna’s mRNA-1608, a therapeutic vaccine candidate for HSV-2, is currently in Phase 1/2 clinical trials. This vaccine uses messenger RNA technology to instruct cells to produce three key HSV-2 glycoproteins, inducing a strong antibody and cell-mediated immune response.
Another element is next-generation antiviral drugs, such as helicase-primase inhibitors like ABI-5366. These target viral proteins involved in replication and are designed for less frequent dosing than current daily suppressive therapy, interfering with the viral life cycle at different stages.
Eradicating the Virus Through Gene Editing
The most advanced research path aiming for a complete, or “sterilizing,” cure involves gene editing technology. This approach seeks to locate and destroy the viral DNA dormant within the nerve cells, primarily using the CRISPR/Cas9 system. The Cas9 enzyme acts as molecular scissors, guided by RNA sequences designed to match specific parts of the HSV episome. By targeting multiple locations on the viral genome, researchers force the viral DNA to be cut repeatedly. This prevents the cell’s repair mechanisms from salvaging it, effectively destroying the virus’s genetic blueprint.
The gene-editing machinery is delivered into nerve cells using specialized transport vehicles, such as adeno-associated viruses (AAVs). Preclinical studies in animal models have shown this technique can significantly eliminate latent HSV-1 genomes from the sensory ganglia. Successfully translating this process to human safety and ensuring delivery efficiency in all infected neurons remains the major technical challenge.
The Role of Preventative Vaccines
Separate from research focused on curing an existing infection, a major effort is underway to develop prophylactic, or preventative, vaccines. These vaccines are designed to protect uninfected individuals from acquiring HSV-1 or HSV-2. Historically, developing a successful preventative vaccine has been challenging, with many candidates failing in clinical trials.
New strategies leverage modern technologies, including mRNA platforms, which offer advantages in development speed and the breadth of immune response they can elicit. Preventative vaccines aim to stop the virus from entering cells and prevent it from establishing latency in the nerve ganglia. For example, a trivalent mRNA vaccine, which targets three different viral glycoproteins, has shown promise in animal models by preventing the infection of the dorsal root ganglia. Success in this area would be a major public health victory by halting the spread of the virus to new populations.