Herpes simplex (HSV) is a viral infection caused by the herpes simplex virus, of which there are two types: HSV-1 and HSV-2. HSV-1 is primarily associated with oral herpes, which commonly causes cold sores or fever blisters around the mouth. HSV-2 is typically linked to genital herpes, which affects the genital and anal regions. However, both virus types are capable of infecting either site.
Herpes simplex is a common and highly contagious infection that affects millions of individuals worldwide with an estimated 3.7 billion people under the age of 50 (67%) infected with HSV-1 and 491 million people aged 15–49 (13%) infected with HSV-2, according to the World Health Organization. [citation needed] The virus is transmitted through direct contact with infected skin, saliva, or genital secretions. Following initial infection, the virus remains latent in the body and can periodically reactivate, leading to recurrent episodes of sores or blisters at the site of infection.
Although there is no cure for herpes simplex, antiviral medications such as acyclovir can help reduce the severity and frequency of outbreaks and may decrease the risk of transmission to others.
Herpes Simplex Virus Classification
Herpes simplex virus (HSV) is a highly contagious virus that can cause a range of infections in humans. There are two types of HSV: HSV-1 and HSV-2. Both types of HSV can cause oral and genital herpes, but they differ in their transmission, symptoms, and treatment.
HSV-1: Oral Herpes
HSV-1 is most commonly associated with oral herpes, although it can also cause genital infections. Transmission primarily occurs through oral-to-oral contact, including kissing, sharing utensils, or other exposures to infected saliva or mucosal surfaces. According to the World Health Organization (WHO), an estimated 3.7 billion people under age 50 (approximately 67% of the global population) are infected with HSV-1.
Clinical manifestations typically include herpetic lesions (cold sores or fever blisters) around the lips and mouth. These lesions may rupture, forming painful ulcers that subsequently crust over during the healing process. HSV-1 may also cause herpetic whitlow, herpes keratitis, and in rare cases, herpes encephalitis, a serious infection of the brain.
Although HSV-1 remains latent in the trigeminal ganglion, periodic reactivation can occur, leading to recurrent outbreaks. There is no curative treatment; however, antiviral medications such as acyclovir, valacyclovir, and famciclovir are effective in reducing the frequency and severity of recurrences.
HSV-2: Genital Herpes
HSV-2 is primarily associated with genital herpes, though it can also cause oral infections. It is predominantly transmitted through sexual contact, including vaginal, anal, and oral sex. According to WHO estimates, approximately 491 million people aged 15–49 (13% of the global population in this age group) are infected with HSV-2.
Genital herpes caused by HSV-2 typically presents with painful vesicular or ulcerative lesions on or near the genitalia, anus, or inner thighs. Initial infections are often more severe than recurrences and may be accompanied by systemic symptoms such as fever, lymphadenopathy, and malaise.
Following primary infection, HSV-2 establishes latency in the sacral dorsal root ganglia and may reactivate periodically. As with HSV-1, antiviral therapy can help manage symptoms and reduce viral shedding. Consistent use of barrier protection methods, such as condoms, and abstinence during symptomatic outbreaks are recommended to reduce transmission risk. Suppressive antiviral therapy can also lower the likelihood of asymptomatic viral shedding.
Epidemiology of Herpes Simplex
According to the World Health Organization (WHO), approximately 67% of the global population under the age of 50 (about 3.7 billion people) are infected with HSV-1, and around 11% (an estimated 491 million people aged 15–49) are infected with HSV-2. The prevalence of herpes simplex varies significantly by geographic region, socioeconomic status, and age, with developing countries generally showing higher seroprevalence, likely due to earlier age of exposure, limited access to healthcare, and low public awareness.
HSV-1 is primarily transmitted through oral-to-oral contact, such as kissing, sharing food utensils, or toothbrushes, and typically causes oral herpes, characterized by cold sores or fever blisters around the mouth. HSV-2, by contrast, is almost exclusively transmitted through sexual contact, including genital, anal, and oral sex, and is the leading cause of genital herpes. However, due to changes in sexual practices, HSV-1 is increasingly being detected in genital infections, particularly in young adults. Both HSV-1 and HSV-2 can be transmitted through any form of skin-to-skin contact, including during asymptomatic viral shedding, which means transmission can occur even when no visible symptoms are present.
Once a person is infected, the virus establishes latency in the sensory nerve ganglia—the trigeminal ganglion for HSV-1 and the sacral ganglia for HSV-2—where it remains dormant for life. Periodically, the virus can reactivate, often triggered by stress, illness, fever, sunlight, or immunosuppression, leading to recurrent outbreaks. The frequency and severity of these outbreaks vary from person to person and may decrease over time. Some individuals may experience frequent, painful recurrences, while others may have no noticeable symptoms after the initial infection.
Although herpes simplex infections are not typically life-threatening in healthy individuals, they can cause significant physical discomfort and emotional distress due to the recurrent nature of the disease and associated social stigma. In immunocompromised patients, newborns, or those with co-existing infections like HIV, HSV infections can lead to severe complications, including encephalitis, disseminated infection, or neonatal herpes, which carries a high mortality rate if untreated.
Prevention strategies include safe sex practices, such as consistent use of condoms or dental dams, regular STI screening, avoiding contact during active outbreaks, and maintaining good hygiene. While antiviral medications like acyclovir, valacyclovir, and famciclovir do not cure the infection, they can reduce symptom severity, shorten the duration of outbreaks, and lower the risk of transmission.
Pathophysiology
Viral Structure and Genome
Herpes simplex virus (HSV) is a large, enveloped, double-stranded DNA virus belonging to the Alphaherpesvirinae subfamily within the Herpesviridae family. The two major serotypes, HSV-1 and HSV-2, share about 50% genomic homology but differ in typical transmission routes and site of infection.
The viral particle measures approximately 150–200 nm in diameter. It consists of an icosahedral capsid that encloses the linear DNA genome, a protein-rich tegument layer, and a lipid bilayer envelope derived from the host cell membrane. This envelope is studded with multiple viral glycoproteins (such as gB, gC, gD, gH, and gL), which are essential for host cell entry, fusion, and immune evasion.
The HSV genome is approximately 152 kilobase pairs in length and encodes over 80 proteins. These include immediate-early, early, and late proteins involved in viral replication, immune modulation, structural assembly, and host-cell manipulation.
Replication Cycle
The HSV replication cycle is a multistep process that begins with viral attachment to the host cell surface. Glycoproteins on the viral envelope interact with host receptors such as heparan sulfate, nectin-1, and HVEM (herpesvirus entry mediator). This is followed by fusion of the viral envelope with the host plasma membrane or endosomal membrane, resulting in the release of the capsid and tegument proteins into the cytoplasm.
The viral capsid is transported to the nuclear pore complex via the host’s microtubule network. Once at the nuclear membrane, the viral DNA is released into the nucleus. Inside the nucleus, the viral genome is transcribed and replicated through rolling circle replication. Immediate-early genes regulate the expression of early genes involved in viral DNA synthesis, while late genes encode structural proteins for virion assembly.
Viral particles are assembled in the nucleus, transiently acquire envelopes during nuclear egress, and undergo final envelopment in the Golgi apparatus. Mature virions are released from the host cell through budding and exocytosis. The full replication cycle typically completes in 18–20 hours, with each cell producing thousands of viral particles.
Cellular Entry and Egress
HSV infects a wide range of cell types, including epithelial cells, fibroblasts, neurons, and immune cells. During initial infection, the virus must overcome extracellular barriers and fuse with the host cell membrane. After entry, HSV is capable of infecting sensory neurons, where it travels retrogradely to the cell bodies located in the trigeminal ganglia (for HSV-1) or sacral ganglia (for HSV-2).
In neurons, the virus establishes lifelong latency by circularizing its genome and expressing latency-associated transcripts (LATs), which suppress lytic gene expression and inhibit apoptosis. The virus remains transcriptionally silent in this latent phase but retains the ability to reactivate in response to various triggers such as psychological stress, fever, ultraviolet radiation, and immunosuppression.
Reactivation leads to anterograde transport of the virus back to peripheral tissues, where active replication resumes, resulting in clinical lesions and potential transmission.
During egress, HSV must bypass cellular defenses including the nuclear membrane, cytoplasmic vesicles, and immune detection. Viral proteins such as ICP0 and ICP34.5 play key roles in evading host immune responses by downregulating MHC class I molecules, inhibiting interferon signaling, and promoting cell-to-cell spread, which limits exposure to neutralizing antibodies.
Clinical Manifestations
Herpes simplex virus (HSV) infections present a broad spectrum of clinical manifestations, ranging from asymptomatic cases to severe complications affecting various body systems. The clinical course is largely determined by the type of HSV (HSV-1 or HSV-2), the site of infection, and the host immune response.
Primary Infection Symptoms
The first time someone is infected with HSV is usually the most intense. Symptoms usually appear within 2 to 20 days after contact with the virus. The signs vary depending on where the virus enters the body and how healthy the person is.
Typical signs of a first infection include:
- Painful blisters or sores on the mouth, genitals, anus, or skin
- These blisters may break open and turn into shallow, red-rimmed sores
- Fever, tiredness, body aches, headaches, and swollen glands are common
- In women, genital HSV-2 may also cause painful urination and inflammation of the cervix
The first episode can last 2 to 4 weeks and may cause emotional stress due to pain and embarrassment.
Interestingly, up to 80% of people with HSV-2 (which usually affects the genitals) have no noticeable symptoms, but they can still spread the virus to others without knowing.
Recurrent Infection Symptoms
After the first infection, the virus doesn’t leave the body. Instead, it hides in nerve cells near the spine and can become active again later. This reactivation can happen for several reasons, including:
- Stress
- Fever or other illness
- Menstrual period
- Weakened immune system
- Sunlight exposure (for cold sores on the mouth)
When the virus becomes active again, symptoms are usually milder than the first time and often include:
- A tingling, burning, or itching feeling just before small blisters appear
- The blisters crust over and heal in about 7 to 10 days, usually without scarring
Genital HSV-2 tends to come back more often than oral HSV-1, with HSV-2 recurring around 4–5 times a year, and HSV-1 only about once a year.
Herpetic Whitlow
This is a herpes infection that affects the fingers, often seen in healthcare workers or adults exposed through sexual contact. It causes:
- Red, swollen fingers
- Small blisters grouped together
- Pain, fever, and swollen lymph nodes
It can come back and may need antiviral medication like acyclovir for treatment and prevention.
Herpes Gladiatorum
This type is common in athletes, especially those in contact sports like wrestling or rugby, where there is a lot of skin-to-skin contact.
Symptoms include:
- Blisters on the face, neck, shoulders, or chest
- Fever, sore throat, and swollen glands
Outbreaks can spread rapidly among teams, sometimes affecting up to 30% of players. Preventing the spread includes keeping infected athletes away from matches and maintaining good hygiene.
Ocular Herpes
Ocular herpes, usually caused by HSV-1, affects the eye and can lead to serious vision problems if not treated.
Signs include:
- Blisters on the eyelid (blepharitis)
- Red, watery eyes (conjunctivitis)
- Pain, blurred vision, light sensitivity, and eye ulcers (keratitis)
Repeated infections can damage the cornea (the clear front part of the eye), sometimes leading to permanent vision loss.
Treatment includes eye drops with antiviral medicine and oral antiviral pills. Steroid eye drops should only be used if prescribed by an eye specialist, as they can make things worse if used incorrectly.
Diagnostic Procedures
Viral Culture
Viral culture is a laboratory test that involves growing a sample of cells or fluid from a herpes simplex lesion to determine if the virus is present. This test is most effective when taken from a fresh lesion, as the virus becomes less detectable as the lesion heals. The results of this test can take several days to come back.
Polymerase Chain Reaction (PCR)
PCR is a molecular biology technique that detects the genetic material of the herpes simplex virus. This test is highly sensitive and can detect the virus even when there are no visible symptoms. PCR is often used to confirm a diagnosis of herpes simplex, especially when there are no visible symptoms.
Serological Testing
Serological testing involves testing a person’s blood for antibodies to the herpes simplex virus. This test can determine if a person has been previously infected with the virus, but it cannot determine if a person is currently infected. Serological testing is not typically used to diagnose herpes simplex, but it can be useful in certain situations, such as when a person has a history of recurrent outbreaks.
Tzanck Smear
A Tzanck smear is a microscopic examination of a sample of cells from a herpes simplex lesion. This test can be used to confirm a diagnosis of herpes simplex, but it is not as accurate as other diagnostic tests. The results of this test can be obtained quickly, often within a few hours, but it is not as sensitive as other tests and may produce false negative results.
Treatment and Management
Antiviral Medications
Antiviral therapy remains the cornerstone of treatment for herpes simplex virus (HSV) infections. While there is currently no cure, antivirals help control viral replication, shorten the duration of active lesions, and reduce the frequency and severity of recurrences. They are also effective in decreasing viral shedding, thus lowering the risk of transmission to sexual partners or neonates.
The most commonly prescribed antiviral agents include:
- Acyclovir – the first antiviral developed for HSV, and widely used due to its safety and efficacy. It is available in oral, topical, and intravenous forms.
- Valacyclovir – a prodrug of acyclovir with greater oral bioavailability, allowing for less frequent dosing. It is often preferred for both episodic and suppressive therapy.
- Famciclovir – a prodrug of penciclovir, effective for HSV-1 and HSV-2, and also suitable for recurrent episodes.
For first-episode genital herpes, a 7–10 day course of antivirals is typically recommended. In cases of frequent recurrences (defined as ≥6 outbreaks per year), daily suppressive therapy may reduce recurrences by up to 80% and asymptomatic shedding by approximately 70–90%, according to clinical trials.
Intravenous acyclovir is used in severe infections, such as herpes encephalitis, neonatal herpes, or in immunocompromised patients, where systemic involvement or disseminated disease is a concern.
Resistance to acyclovir and related drugs is rare in immunocompetent individuals but may occur in immunosuppressed populations (e.g., transplant recipients or people with HIV/AIDS), necessitating alternative agents like foscarnet or cidofovir.
Pain Management
Symptom relief is essential, especially during primary infection, which is often the most painful. Pain from HSV lesions can significantly impact daily functioning and quality of life, particularly in genital infections.
Management includes:
- Over-the-counter (OTC) analgesics, such as: Acetaminophen (paracetamol) – useful for pain and fever. Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen – reduce inflammation and provide analgesia.
- Topical anesthetics such as lidocaine 2% gel or benzocaine can be applied directly to lesions to provide localized relief.
- Sitz baths with warm water may help soothe genital lesions and promote healing.
- In moderate to severe pain, prescription analgesics such as codeine or tramadol may be used with caution, especially in individuals experiencing systemic symptoms or extensive ulcerations.
Prevention and Control Strategies
Safe Sex Practices
Practicing safe sex remains one of the most effective methods to prevent the transmission of herpes simplex virus (HSV-1 and HSV-2). While HSV-1 is commonly acquired through oral contact, HSV-2 is primarily transmitted through genital-to-genital contact during sexual activity.
Key strategies include:
- Consistent use of condoms or dental dams, which can reduce the risk of HSV transmission by approximately 30%–50% according to the Centers for Disease Control and Prevention (CDC). However, because HSV can be transmitted via skin-to-skin contact with areas not covered by condoms, complete protection is not guaranteed.
- Avoiding sexual contact during symptomatic outbreaks, which are marked by lesions, tingling, or pain in the affected area.
- Suppressive antiviral therapy (e.g., daily valacyclovir) for infected individuals, especially those in discordant relationships (i.e., one partner is HSV-positive, the other is not), has been shown to reduce transmission risk by about 48%.
- Open partner communication and routine STI screening, particularly for sexually active individuals with multiple partners, can help reduce overall transmission rates.
Studies show that approximately 50%–90% of genital HSV-1 infections are now acquired through oral-genital contact
Infection Control in Healthcare Settings
Though rare, HSV transmission in healthcare environments can occur, especially in the context of neonatal herpes, nosocomial infections, or occupational exposure among healthcare workers.
To minimize the risk:
- Standard precautions must be followed, including the use of gloves, gowns, and proper hand hygiene when caring for patients with active lesions.
- Healthcare workers should avoid direct contact with mucous membranes or compromised skin unless appropriately protected.
- Decontamination of instruments and surfaces is crucial, as HSV can survive for short periods (several hours to a few days) on inanimate surfaces, particularly under moist conditions.
- Infected patients with active mucocutaneous lesions, especially immunocompromised or neonatal cases, should be isolated when necessary and treated promptly with antiviral agents to reduce viral shedding and prevent spread.
Vaccine Development
Despite decades of research, no licensed vaccine currently exists for HSV-1 or HSV-2. The complexity of HSV immune evasion mechanisms, including latency and immune suppression, has posed challenges for vaccine development.
However, several promising vaccine candidates are under preclinical and clinical evaluation, including:
- Subunit vaccines: targeting glycoproteins like gD2 and gB, which are involved in viral entry.
- DNA-based vaccines: encoding HSV antigens to stimulate both humoral and cellular immunity.
- mRNA vaccines: following the success of mRNA technology in COVID-19 vaccines, researchers are exploring similar platforms for HSV.
- Live-attenuated and replication-defective vaccines: designed to provoke robust immune responses without causing disease.
A notable trial published in The New England Journal of Medicine (2012) tested a glycoprotein D-based vaccine, which showed partial protection against HSV-1, but not HSV-2, in women. Current trials (as of 2025) are focusing on combination strategies and new delivery systems to improve efficacy.
If successful, a prophylactic HSV vaccine could dramatically reduce global disease burden, especially in low- and middle-income countries, where HSV prevalence exceeds 80% in some regions and access to antivirals is limited.
Psychosocial Impact
Herpes simplex virus (HSV) infection, particularly genital herpes, exerts a profound psychosocial burden on affected individuals. Despite being a medically manageable condition, the social stigma, emotional distress, and relationship challenges it brings are often underestimated.
Emotional and Mental Health Consequences
The diagnosis of HSV frequently triggers feelings of shame, guilt, embarrassment, and fear of rejection. This is largely due to the misconceptions and social stigma associated with sexually transmitted infections (STIs), even though HSV is extremely common. According to the World Health Organization (WHO), over 3.7 billion people under age 50 have HSV-1, and approximately 491 million people aged 15–49 are infected with HSV-2 globally.
Studies show that individuals with genital herpes have a 2–3 times higher risk of experiencing depression and anxiety compared to the general population. In a U.S.-based survey published in Sexually Transmitted Diseases, more than 70% of individuals with newly diagnosed genital HSV reported significant distress during the first six months post-diagnosis.
These emotional responses are not limited to the initial diagnosis. Recurrent outbreaks, which are unpredictable and sometimes painful, can reinforce feelings of helplessness and loss of control over one’s body and health.
Impact on Sexuality and Relationships
HSV can significantly affect how individuals view their sexual identity, behavior, and intimate relationships. Concerns about disclosure, fear of rejection, or guilt over possibly transmitting the virus often lead to:
- Avoidance of sexual activity or reduced sexual frequency.
- Difficulty initiating or maintaining intimate relationships.
- Internalized stigma that leads to lowered self-esteem and social withdrawal.
Even in long-term relationships, the presence of HSV can create tension, particularly in cases where one partner is uninfected. Disclosure of HSV status is a complex emotional process, and individuals often express concern about being labeled or misunderstood.
Coping Strategies and Clinical Support
Healthcare professionals play a critical role in addressing the psychosocial impact of HSV. Beyond medical treatment, comprehensive care should include:
- Empathetic communication at the time of diagnosis to dispel myths and provide factual information.
- Psychological counseling or referral to mental health professionals, especially for patients showing signs of depression, anxiety, or emotional distress.
- Peer support groups (in-person or online) that connect individuals with shared experiences can significantly alleviate feelings of isolation and improve quality of life.
- Education about suppressive antiviral therapy, which can reduce outbreak frequency and transmission risk, often provides psychological relief and restores a sense of control.
- Normalizing HSV as a common, manageable condition and framing the diagnosis within the context of holistic sexual health can help mitigate long-term psychosocial harm.