The Herpes Simplex Virus type 2 (HSV-2) is a common viral infection, primarily responsible for genital herpes. An estimated 520 million people aged 15 to 49 carry the virus globally, which causes painful blisters or ulcers that can recur over time. While the body mounts a defense to control outbreaks, achieving sterilizing immunity—the complete and permanent elimination of the virus—is not possible because the virus has evolved specific mechanisms to evade the host’s complete immune response.
How HSV-2 Evades Complete Immune Clearance
The human immune system is highly effective at managing and controlling an initial HSV-2 infection, but it is unable to eliminate the virus. This is because HSV-2 is a neurotropic virus, meaning it has the ability to infect nerve cells and establish a state known as latency. Latency is the biological reason why a person cannot achieve sterilizing immunity.
Following initial infection at the skin or mucosal surface, the virus travels backward along the nerve axon to the cell body of a sensory neuron. HSV-2 establishes its permanent home in the sacral dorsal root ganglia (DRG), clusters of nerve cells located near the base of the spine. Once inside the neuron’s nucleus, the viral DNA circularizes and remains dormant as an episome.
This latent state renders the virus invisible and inaccessible to the circulating immune cells. Neither antibodies, which patrol the bloodstream, nor cytotoxic T-cells, which destroy infected cells, can enter the shielded nerve cell to eradicate the dormant virus. The immune system can only respond when the virus reactivates and travels back down the axon to the skin surface.
Recurrence, or an outbreak, occurs when the latent virus is triggered by various factors, such as stress or illness, and travels forward to the periphery. The resulting visible lesions or periods of asymptomatic shedding are the times when the virus becomes vulnerable to the host’s immune defenses and is most transmissible. While the body’s immune response quickly moves to suppress the replication and clear the active infection at the skin, the latent reservoir in the nerve cells remains undisturbed, allowing for future recurrences.
Strategies for Preventing Initial Acquisition
Prevention focuses on external strategies to reduce the risk of initial acquisition. Consistent use of barrier methods, such as latex condoms, is one of the primary methods for reducing the risk of transmission. Condoms significantly decrease exposure risk to the virus, but they do not provide absolute protection because transmission can still occur through contact with skin in the genital or anal areas not covered by the barrier.
A person with HSV-2 is most contagious when lesions are present, so abstaining from sexual activity during an active outbreak or when prodromal symptoms—like tingling, itching, or burning—are felt is an effective behavioral prevention measure. Transmission can also occur during asymptomatic viral shedding, which is when the virus is present on the skin surface without causing visible symptoms. This highlights the importance of combining prevention methods.
Antiviral suppressive therapy offers a pharmaceutical strategy for reducing the risk of acquisition in uninfected partners. For heterosexual couples where one partner has HSV-2 and the other does not, daily use of an antiviral medication like valacyclovir can reduce the risk of transmission by approximately 50%. This therapy works by reducing the frequency of both symptomatic and asymptomatic viral shedding from the source partner.
Open disclosure of HSV-2 status and type-specific serologic testing are important for managing risk within sexual relationships. When suppressive antiviral therapy is combined with consistent condom use and safer sex counseling, the risk of symptomatic HSV-2 acquisition can be reduced by as much as 75%.
The Search for Therapeutic and Preventative Vaccines
Research toward developing artificial immunity has focused on vaccination, driven by the biological failure to achieve natural sterilizing immunity. Current research focuses on two distinct types of vaccines: prophylactic and therapeutic. A prophylactic vaccine is designed to prevent a person who is currently uninfected from acquiring the virus, requiring the induction of a potent antibody response to block entry into the body.
A therapeutic vaccine is aimed at people already infected with HSV-2, with the goal of reducing the frequency and severity of their outbreaks and minimizing viral shedding. This type of intervention would need to stimulate a strong, localized T-cell response to better control the virus when it reactivates. Historically, many vaccine candidates, including glycoprotein D2 subunit vaccines, have been unsuccessful in human clinical trials, failing to prevent HSV-2 infection or disease.
The challenges for researchers remain significant, largely because the virus hides so effectively in the nervous system. Efforts continue with promising new approaches, including novel mRNA vaccine candidates that aim to induce a strong immune response against the virus. Ongoing research holds the potential for future interventions that could either prevent initial infection or offer a functional cure by drastically limiting recurrence and transmission.