Herpes Simplex Virus 1 and 2

Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae.
Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces,
including the mouth, lips, eyes, and genitals. Typical mucocutaneous infections are characterized by
an acute localized appearance of clusters of small, painful vesicles on an erythematous base.
Although overlap exists, HSV-1 is classically associated with oropharyngeal lesions, whereas HSV-2 is
mostly responsible for genital herpes, an STI. Systemic and severe infections including encephalitis,
meningitis, and neonatal herpes may also occur. The diagnosis is made based on clinical presentation
and history, which can be confirmed by the microscopic examination of a stained smear of a fresh
vesicle, nucleic amplification test using PCR, direct immunofluorescence, or serologic tests. The
therapy for mucocutaneous lesions is usually symptomatic, but antiviral therapies involving acyclovir,
valacyclovir, or famciclovir are useful if given early, and are always part of the therapy for serious
systemic infections.

Last updated: October 5, 2022

CONTENTS

Classification
General Characteristics and Epidemiology
Pathogenesis
Diseases caused by HSV-1
Diseases Caused by HSV-2
Diagnosis
Management
Comparison of Herpesviruses
Differential Diagnosis
References
Classification

DNA virus identification:

Viruses can be classified in many ways. Most viruses, however, will either have a genome formed by DNA or RNA.
Viruses with a DNA genome can be further characterized by whether that DNA is single or double stranded. If the
viruses are covered by a thin coat of cell membrane (usually taken from the host cell), they are called “enveloped”
viruses. If that coat is absent, the viruses are called “naked” viruses. Some of the enveloped viruses translate their
DNA into RNA before it is incorporated into the host cell’s genome.

Image by Lecturio.

General Characteristics and Epidemiology

Basic features of herpes simplex virus
Taxonomy:
Family: Herpesviridae
Subfamily: Alphaherpesvirinae
Genus: Simplexvirus
DNA virus
Double stranded
Linear
Encodes approximately 70 proteins
Structure:
Core (contains genome)
Icosahedral nucleocapsid
Tegument (contains viral proteins and enzymes)
Envelope and glycoprotein spikes
Clinically relevant species
Two types have been recognized to cause infections:
 HSV-1 (tropism for oral epithelium)
HSV-2 (tropism for genital epithelium)

Epidemiology
HSV-1:

Prevalent worldwide
Affects approximately 66% of the population
Seroprevalence:
Individuals 0–49 years of age:
47% in the US
Up to 90% in low-income countries
In children in the US:
6–7 years: 26%
12–13 years: 36%
No gender preference
Becoming more common as a cause of genital herpes
Most common cause of acute, nonepidemic viral encephalitis in the US

HSV-2:

Prevalent worldwide
More common in low-income countries
Seroprevalence:
Individuals who are 14–49 years old in the US: approximately 16%
Increases with age and the number of sexual partners
Gender:
Women: 21%
Men: 12%
Race:
Non-Hispanic Blacks: 39%
Non-Hispanic Whites: 12%

Neonatal herpes infection:

A rare complication of maternal genital herpes infection

Occurs in about 1 in 3,200 deliveries in the US
Most likely to occur in women who acquire primary genital herpes infection and, thus, lack
maternal antibodies at or near the time of delivery

Pathogenesis
Reservoir
Humans are the main reservoir.

Transmission
HSV-1:
 Close contact with oral secretions of individuals who are actively shedding the virus
May also be transmitted via unapparent or asymptomatic lesions
Can be transmitted through oral sex to uninfected partners

HSV-2:

Sexual contact:
Risk is higher with male than with female source partners.
70% of successful transmissions occur during periods of asymptomatic viral shedding.
Contact with infected secretions
Perinatal transmission:
Usually occurs during vaginal birth
In utero infections can occur in primary infections.

Pathophysiology
Primary infection:

Primary infection:
Occurs in individuals with no preexisting antibodies for HSV-1 or HSV-2
Different from non-primary 1st-episode: a herpes infection in a patient with preexisting
antibodies to the alternate serotype
Example: 1st episode of a perioral lesion of HSV-1 in a patient who has preexisting
antibodies to HSV-2
Patients exhibit attenuated symptoms and signs similar to those in reactivation
lesions, with fewer lesions and less severe systemic symptoms.
Virus must encounter mucosal surfaces or broken skin (intact skin is resistant).
Virus attaches to and enters epithelial cells through interactions between the viral surface
glycoproteins and cellular HSV receptors (e.g., nectin-1).
Vesicular lesions of the epidermis are produced → release of infectious virions during the
lytic/reproductive phase

Lifetime latency:

Definition: the persistence of viral genomes in cells that do not produce infectious virus
Viral nucleocapsids are transported along sensory axons to the neuronal cell bodies →
establishment of latent infection:
Trigeminal ganglia in oropharyngeal infections
Sacral ganglia in genital infections
Virus remains latent in the nuclei of nerve cells.
Only latency-associated viral RNA transcripts (LATs) are synthesized (no viral proteins are
produced).
LATs appear to confer resistance to apoptosis by silencing lytic gene expression through
heterochromatin formation, which prevents transcription.
HSV avoids cellular and humoral immune recognition by:
Inhibiting the class I MHC recognition pathway
Producing decoy receptors that bind the Fc domain of Igs and inhibit
complement activation
Infecting dendritic cells that help in antiviral immune responses

Reactivation:
 Signifies the transition of a virus from its latent state to lytic replication state in the nerve ganglia
The virus moves by anterograde axonal transport to epithelial cells at the original infected site.
Replication occurs within epithelial cells:
Formation of 1 or more typical clusters of vesicles
Can also be clinically unapparent and involve the asymptomatic shed of virions
Recurrent eruptions are usually:
Less severe
Occur less frequently over time
Occurs in immunocompetent individuals because HSV has multiple immune-evasion
mechanisms
Factors favoring reactivation/frequency of reactivation:
Immunosuppressed states:
Transplant recipients
Patients with cancer
Patients with AIDS who have low CD4 counts (HSV requires intact
cellular immunity to be normally contained)
Excessive sunlight
Febrile illnesses
Physical (e.g., dental procedures) or emotional stress
Elderly
Unknown stimuli

Diagram summarizing the pathogenesis of HSV-1 and -2 infections

Image by Lecturio. License: CC BY-NC-SA 4.0

Pathology
Herpes simplex viruses cause cytolytic infections that form the basis of all pathologic changes:
necrosis of infected cells together with the inflammatory response
Gross:
Grouped vesicles on an erythematous base
Later become pustules and form crusts that heal without scarring because cytopathic
effects are limited to the epidermis
Microscopic:
Infected keratinocytes become multinucleated (from cell fusion) and acantholytic
(separated from each other).
Distinct intranuclear inclusions (“Cowdry type A inclusions” = viral replication proteins and
virions that push chromatin to the edge of the nucleus)
Epidermal necrosis or full-thickness acantholysis (causes blistering)
Dermal nerve twigs may have acute and chronic perineural inflammation with occasional
Schwann cell hypertrophy and frank neuronal necrosis.
Diseases caused by HSV-1
A number of conditions are caused by HSV. The infections listed below are most commonly
caused by HSV-1. Note: HSV-2 can also be (though often less commonly) associated with many
of these diagnoses.

Asymptomatic infection
Only 20%‒25% of patients with HSV-1 antibodies have a positive clinical history of oral-labial or
genital infections.

Oral infections
Gingivostomatitis:
 Commonly caused in children by a primary infection
Signs and symptoms:
Fever
Painful vesicular lesions:
Occur on the oral and pharyngeal mucosa
Ulcerate rapidly
Gingivitis with extension to the lips and cheeks
Pharyngitis
Cervical lymphadenopathy
Systemic symptoms:
Fever
Malaise
Myalgias

Pharyngitis:

Commonly caused in adults by a primary infection

Signs and symptoms:
Pharyngeal edema and pain
Tonsillar exudate
Oral lesions:
Exudative
Ulcerative
Cervical lymphadenopathy
Systemic symptoms

Herpes labialis:

Recurrent reactivation infection

Signs and symptoms:
Prodrome:
Approximately 24 hours before the outbreak, painful lesions develop at the lip
border (“vermilion border”).
Pain
Burning
Tingling
Pruritus
Lesions:
Consist of vesicles or localized oral-labial ulceration (“cold sores” or “fever
blisters”)
Decrease in pain after 24 hours
Healing and crust formation in 5–8 days
Rarely associated with systemic symptoms
Genital infection
Primary genital HSV-1 infections:
Bilateral genital ulcerations
Tender lymphadenopathy
Fever
Headache
Myalgias
Autonomic dysfunction (urinary retention or constipation)
Sensory disturbances (hyperesthesia or anesthesia of the perineum)
Reactivation of genital HSV-1:
More common in the 1st year after infection
Multiple recurrences are rare (unlike genital HSV-2 infections).

Other cutaneous manifestations

Herpetic whitlow:
 Infection of the finger from inoculation of the virus through a break in the skin
Seen in:
Children after autoinoculation
Adolescents in association with genital HSV
Healthcare personnel (dentists, home healthcare workers)
Signs and symptoms:
Single or cluster of vesicles:
Usually clear with erythematous base → can become turbid
Evolve into a shallow ulcer → crust
Gradually heal in 2–3 weeks
Burning or tingling pain
Flu-like symptoms can occur.
Differentiate from bacterial infections (paronychia), as surgical incision is not required.

Herpes gladiatorum:

Skin infection of the face, neck, and arms of wrestlers and rugby players
Vesiculopustular rash → ulceration

Erythema multiforme:

Immune-mediated disorder
Signs and symptoms:
Cutaneous target lesions
Mucosal erythema and erosions or bullae (painful)

Eczema herpeticum:

HSV-1 infection superimposed on skin lesions from atopic dermatitis (particularly in patients on
immunosuppressive therapy)
Signs and symptoms:
Pain and vesicular skin lesions
Can spread rapidly if untreated
Eye infections
Eye infections occur in < 5% of patients with HSV-1 infections, leading to vision loss and/or
blindness.

Keratitis:
 Infection of the corneal epithelium
Leading cause of corneal blindness in high-income countries
Signs and symptoms:
Pain
Foreign-body sensation
Visual blurring
Tearing
Chemosis
Conjunctivitis
↓ Corneal sensation
Characteristic dendritic lesions of the cornea:
Corneal ulcer with a branching pattern
Seen on slit-lamp examination
Recurrent infections are common.
Stromal scarring can result.

Acute retinal necrosis:

Rare, potentially blinding, necrotizing retinitis

Occurs in:
Immunocompetent hosts
Pregnant women
Patients with an HIV infection
Signs and symptoms:
↓ Vision
Eye redness
Floaters
Photophobia
Some patients may have periorbital pain.

Conjunctivitis and blepharitis:

Unilateral
Vesicles on the lid margin
Chemosis
Edema of the eyelids
Tearing

Chorioretinitis (posterior uveitis):

From disseminated HSV infections

Seen in neonates or immunosuppressed individuals
Signs and symptoms:
Blurred, distorted, or loss of vision
Scotoma
Floaters
Neurologic syndromes
Encephalitis:

Usually unilateral, involving the temporal lobe and insular cortex (board exam question)
High rate of morbidity and mortality
Signs and symptoms:
Fever
Headache
Seizures
Focal neurologic signs
Impaired consciousness

Aseptic meningitis:
 More commonly associated with HSV-2 infections
Signs and symptoms:
Fever
Headache
Photophobia
Meningismus

Other manifestations:

Bell's palsy: temporary inability to control the facial muscles on the affected side of the face
Autonomic dysfunction: presents as urinary retention during a primary genital infection
Transverse myelitis: a demyelinating inflammation of both sides of 1 section of the spinal cord

Respiratory tract infections

Epiglottitis or laryngitis (herpetic croup):

May occur in children

Self-limiting condition
Signs and symptoms:
Nonproductive cough
Stridor

HSV pneumonitis:

Rare
Usually occurs in immunocompromised patients
Considered an AIDS-defining condition
Occurs following tracheobronchitis
Signs and symptoms:
Dyspnea
Cough
Fever
Wheezing

Gastrointestinal disease
HSV esophagitis:

Usually seen in immunocompromised hosts

Considered an AIDS-defining condition
Spread by either:
Direct extension from the oropharynx
Reactivation and spread through the vagus nerve to the mucosa
Signs and symptoms:
Odynophagia
Dysphagia
Retrosternal chest pain

Fulminant hepatitis:

Rare
Associated with disseminated disease
Caused by both HSV-1 and HSV-2
Only 30% of patients have typical skin lesions.
Diseases Caused by HSV-2
The conditions listed below are most commonly associated with HSV-2 infections. Again, keep in
mind that HSV-1 can also be associated with many of these diagnoses.

Genital infection
Primary genital HSV-2 infections:

Average incubation period: 4 days (range 2–12 days)

Viremia is more common (24%) than in reactivation cases.
Can be asymptomatic, or present with mild or severe symptoms:
Painful genital ulcers:
Clusters of 2–4-mm vesicles containing clear fluid
Become pustules that rupture → erosions or superficial ulcers with scalloped
borders
Heal without scarring
Dysuria
Fever
Tender local inguinal lymphadenopathy
Headache

Non-primary 1st episode infection (reactivation):

Frequency of recurrences:
Earlier and more frequent recurrences if the primary infection had lasted > 5 weeks
More common with HSV-2 than HSV-1
More common in immunosuppressed patients
Signs and symptoms:
May be symptomatic or asymptomatic
Prodrome: mild tingling or shooting pains in the buttocks, legs, and hips
Fewer lesions and less severe systemic symptoms
Penile blisters (arrows) due to a recurring herpes simplex-2 virus (HSV-2) infection

Image: “Penile blisters (arrows), due to a recurring herpes simplex-2 (HSV-2) virus infection” by CDC/ Susan Lindsley. License: Public
Domain

Extragenital manifestations
Aseptic meningitis
Benign recurrent aseptic meningitis (Mollaret's meningitis):
> 3 episodes of meningitis symptoms
Followed by spontaneous resolution
Sacral ANS dysfunction: causes urinary retention
Sacral radiculitis:
Acute urinary retention with loss of sacral sensation
Occurs in severe primary infections
Transient, but requires catheterization
Hepatitis
Proctitis: more common in men who have sex with men (MSM)

Diagnosis
PCR:
Preferred method of diagnosis
Can be used to detect viral DNA
Can be used to identify HSV serotypes
Extremely high sensitivity (98%) and specificity (99%)
Positive findings early in the course of illness
Samples can be obtained from:
Unroofed vesicular lesions
Intraocular fluid (acute retinal necrosis)
Urethral, rectal, or cervical swabs
CSF
Blood (useful for fulminant neonatal infections, hepatitis)
Viral cultures:
Less sensitive than PCR
Depends on the quantity of virus
Tissue biopsy:
Sites:
Skin
Lung
Liver
Esophagus
Can be diagnosed based on histologic appearance and confirmed using
immunohistochemical or molecular methods
Tzanck smear:
Procedure:
Specimen is obtained by scraping the base of a vesicle.
Specimen is placed on a slide.
Stained with Giemsa or toluidine blue
Typical cytopathic effects of HSV are observed.
Will show multinucleated giant cells
Low sensitivity and specificity
Cannot differentiate between HSV serotypes
Direct fluorescent antibody testing:
Rapid
Low sensitivity and specificity
Serologic testing:
Limited applications
Titers do not correlate with positive cultures or the presence of lesions.
 Image from a Tzanck smear obtained from a penile lesion:
Multinucleated giant cells are seen, indicating a herpes infection.

Image: “Photomicrograph depicts a Tzanck stained penile lesion specimen” by CDC/ Joe Miller. License: Public Domain

Management
Medical therapy
Antivirals:
 Mechanism of action: nucleoside derivatives that interfere with the synthesis of viral DNA by
inhibiting viral DNA polymerase
Renal function should be monitored.
Uses:
Depends on severity (may not be needed for mild or minimally symptomatic infections)
Treatment of an active infection
Episodic therapy (started at the very 1st sign of prodromal symptoms)
Chronic suppression (for frequent or severe recurrences)
Reduces but does not eliminate viral shedding
Systemic options:
Acyclovir
Valacyclovir
Famciclovir
Topical options (for ocular infections):
Acyclovir
Ganciclovir
Trifluridine (more corneal toxicity)

Analgesics:

Lidocaine
Benzocaine

Immunosuppressed patients
Immunosuppressed patients may have more severe symptoms, higher risk of complications, and
greater risk for developing drug-resistant HSV infections.
Treated with similar regimens as immunocompetent patients, but with higher doses for
suppressive therapy
Patients who are HIV positive and not on antiretroviral therapy (ART) may be prone to immune
reconstitution inflammatory syndrome (IRIS) when treated for HSV infections.
Clinical manifestations worsen initially after the initiation of ART.
Suppressive therapy may be given to prevent IRIS.

Prevention of new HSV infections

Herpes labialis:
Avoid contact with saliva or saliva-contaminated fomites from family members and
intimate partners (e.g., avoid kissing and sharing kitchen utensils and towels).
Healthcare workers:
Universal precautions
Wear gloves during physical examination of a patient with active HSV lesions.
Eye and mouth protection when suctioning or during bronchoscopy
Genital herpes:
Barrier use for oral and genital sex is recommended.
Note: Precautions should be taken by pregnant partners who are HSV negative owing to
the high risk of transmission to the neonate.
Herpes gladiatorum:
Athletes must not participate in contact sports until all herpes lesions are in the dry, crust
stage.
Suppressive oral antiviral therapy has been suggested for all wrestlers regardless of HSV
history, as it markedly reduces the risk of an outbreak (by 85%).
Comparison of Herpesviruses
The table presented below compares and contrasts HSV-1 and HSV-2:

Table: Comparision of herpes simplex viruses

Serotype HSV-1 HSV-2

Transmission Respiratory secretions, saliva Sexual contact, perinatal

Ubiquitous 30% in adulthood
90% in childhood

Lytic infection Mucoepithelial cells Mucoepithelial cells

Latency Trigeminal ganglia Sacral ganglia

Diseases Gingivostomatitis Herpes genitalis

Herpes labialis Neonatal herpes
Keratitis Aseptic meningitis
Conjunctivitis Proctitis
Herpetic whitlow
Encephalitis
Hepatitis
Esophagitis
Pneumonitis

Comparison of viruses in the Herpesviridae family

The table below compares the 9 herpesviruses considered endemic in humans. There are 115
different total known species of herpesviruses, which are grouped into 3 families:

Alpha (infect epithelial cells and produce latent infection in post-mitotic neurons)
Beta (infect and produce latent infection in various cell types)
Gamma (produce latent infection mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans

HHV Common Primary target Latency site Clinical

name cells presentation*
HHV Common Primary target Latency site Clinical
name cells presentation*

1 HSV-1 Mucoepithelial Dorsal root Gingivostomatitis

(alpha cells ganglia Keratitis
group) Herpetic whitlow
Encephalitis
Hepatitis
Esophagitis
Pneumonitis

2 HSV-2 Genital herpes

(alpha Meningitis
group) Proctitis

3 VZV Chickenpox
(alpha Herpes zoster
group)

4 EBV Epithelial Memory B Infectious

(gamma cells cells mononucleosis
group) B cells Hodgkin
lymphoma
Burkitt
lymphoma
Oral hairy
leukoplakia
EBV-associated
gastric cancer

5 CMV Monocytes Hematopoietic CMV

(beta Lymphocytes progenitor mononucleosis
group) Epithelial cells in bone CMV retinitis
cells marrow CMV colitis
CMV
encephalitis
 HHV Common Primary target Latency site Clinical
name cells presentation*

6A, 6B HHV-6 T cells Monocytes Roseola

(beta
group)

7 HHV-7 T cells
(beta
group)

8 Kaposi's Lymphocytes B cells Kaposi sarcoma

(gamma sarcoma- Epithelial
group) associated cells
herpesvirus

*Bold in “clinical presentation” column: AIDS-defining illnesses

VZV: varicella zoster virus

Differential Diagnosis
 Recurrent aphthous ulcers (canker sores): a very common, probably immunologically related
disease of the oral mucosa (and less commonly, the genital mucosa), manifesting as small,
discrete, painful ulcers that heal within 1–2 weeks. Recurrent aphthous ulcers are not preceded
by vesicles and occur only on mucosal surfaces. Diagnosis is clinical, although testing can be
conducted to evaluate for associated conditions (e.g., nutritional deficiencies, inflammatory
bowel disease). Management includes trigger avoidance, symptomatic therapy, and treatment of
underlying etiologies.
Syphilis: a bacterial infection caused by the spirochete Treponema pallidum, which is usually
spread through sexual contact. Primary syphilis can present with hard chancres that initially
present as small red patches. Unlike the vesicles in HSV infections, these chancres (vesicles are
absent) are painless. Diagnosis is made with serology, dark-field examination, and
immunostaining on biopsy. Penicillin G is the antibiotic of choice.
Chancroid: an STI caused by Haemophilus ducreyi. Patients develop painful necrotizing genital
ulcers and inguinal lymphadenopathy. Diagnosis is usually clinical, but PCR and cultures can be
used for confirmation. Management is with macrolide antibiotics.
Other genital, anal, or perianal ulcers: noninfectious causes that are not STI related: yeast,
trauma, carcinoma, aphthae, fixed drug eruption, and psoriasis.
Bacterial pharyngitis: an infection of the pharynx. Patients typically experience a sore throat
and fever. Symptoms are not preceded by a grouped cluster of vesicles as those seen in HSV
infections. Diagnosis can include rapid streptococcal screens to detect group A Streptococcus,
bacterial cultures, and PCR to exclude HSV infections. Treatment includes penicillin or
amoxicillin.
Enterovirus infections (e.g, herpangina): acute febrile illnesses mostly caused by
coxsackievirus A and B, and enterovirus 71. Herpangina is associated with small vesicular or
ulcerative lesions on the posterior oropharyngeal structures (enanthem). Clinical findings and
PCR are used to make the diagnosis. Management is symptomatic.
Infectious mononucleosis: an infection caused by another herpesvirus, the EBV. Clinical
manifestations include fever, tonsillar pharyngitis, and lymphadenopathy. Unlike HSV infections,
mononucleosis is not usually associated with clusters of vesicles. Diagnosis is clinical and
confirmed using heterophile antibody testing or serology. Management is supportive.
Stevens-Johnson syndrome (SJS): a rare, potentially lethal disease that attacks the skin and
mucous membranes. Stevens-Johnson syndrome runs on a spectrum with the more severe form
(toxic epidermal necrolysis (TEN)) and can be triggered by a reaction to a medication or to a
preexisting bacterial or viral infection (including HSV) or illness. Patients present with a flu-like
prodrome and the appearance of cutaneous bullae, followed by sloughing on the face, thorax,
and mucous membranes. Diagnosis is clinical and the management is largely supportive.
Bacterial skin infections with superficial ulceration: infections that can mimic herpetic whitlow.
Bacterial skin infections with superficial ulceration are not preceded by a vesicle and often
involve subepidermal tissues. It is important to differentiate these conditions, as antibiotics and
drainage are not necessary for herpetic whitlow.
Proctitis: besides HSV infections, the differential diagnosis in MSM includes
Neisseria gonorrhoeae, Chlamydia, and T. pallidum infections. The presentation of proctitis can
mimic inflammatory bowel disease. Diagnosis is by PCR, cultures, serology, dark-field
examination, and immunostaining on biopsy.

References