Herpes Simplex Virus (HSV)

• Topic is Herpes Simplex Virus (HSV)
• Presentation by G. Rebecca Jové for Infectious Diseases II Course, MIC 644, Microbiology Division, Revised 2025

Objectives

• Describe the main characteristics of the Herpesviridae family virus.
• Describe populations at risk for herpes infection.
• Learn the clinical manifestation of the family of organisms.
• List the diagnostic procedures used for the clinical manifestations.

Herpes Virus: The Family

• Herpes Simplex 1 is α
• Herpes Simplex 2 is α
• Varicella Zoster Virus is α
• Cytomegalovirus (CMV) is β
• Epstein Barr virus (EBV) is γ
• Human herpes virus 6 is β
• Human Herpes virus 7 is β
• Human herpes virus 8 is γ
• Human B virus is α
• Herpesviruses can remain latent.
• Transmission occurs through direct contact (all), blood products (e.g., EBV, CMV, HHV8), perinatally (HSV1-2, VZV, EBV), or via aerosol (VZV).
• Several herpesviruses have similar clinical manifestations.
• Some herpesviruses are oncogenic, such as EBV and HHV-8.
• Herpesviruses cause intranuclear inclusions in tissues.

HSV Microbiology

• HSV alpha-herpesviruses range from 150 to 200 nm.
• HSV Structurally comprised of four major components: dsDNA, nucleocapsid (viral core), tegument (matrix=protein rich layer), lipid envelope (contains 12 glycoproteins

Epidemiology of HSV

• HSV is the most prevalent STD in the USA.
• HSV 1 and 2 can cause genital infection.
• Genital herpes is primarily caused by HSV-2, but genital HSV-1 is increasing.
• HSV prevalence and incidence are not accurately tracked because it is not a notifiable condition.
• HSV-2 seroprevalence decreased from 18% to 12% between 2000 and 2016.
• Females have a higher seroprevalence of HSV than males (15.9% vs. 8.2%).
• Seroprevalence of HSV increases with age.
• HSV 1 prevalence: 54% vs 48.1%
• HSV 2 prevalence: 18% vs 12.1%

HSV Pathogenesis

• The herpesvirus enters the body through the skin or mucous membranes during primary infection.
• The virus spreads into the dorsal root ganglia.
• The virus can reactivate and result in skin lesions or subclinical shedding.
• The virus migrates within the neuron to the epidermal area.

Genital Herpes: Viral Shedding

• Shedding occurs in the vulva and perianal area in women, and the penile and perianal area in men.
• Higher rates of viral shedding occur in people with frequent outbreaks, during the first year after acquisition, and in primary infections (12 days) compared to recurrent infections (2-3 days).
• Transmission of symptomatic recurrence from men to women is 30%
• Transmission of asymptomatic recurrence from men to women us 70%
• Oral antiviral suppressive therapy (Tx) shortens the duration of viral shedding but does not eliminate it entirely.
• Viral shedding is highest in the first year after infection and decreases with time.
• Transmission is most efficient from infected male to susceptible female partner.

Populations at Risk for HSV-1

• Everyone is at risk for HSV-1.
• Athletes in contact sports (rugby and wrestling) are at risk of herpes gladiatorum.
• Healthcare workers are at risk of herpetic whitlow
• Herpetic whitlow can cause digit involvement, pain, and itching
• HSV-1 affects paramedics, dentists, respiratory therapists, and the general population.
• HSV-2 also affects the general population.

Populations at Risk for HSV-2

• Sexually active individuals are at risk.
• People with multiple sex partners are at risk.
• People with a known infected sexual partner are at risk.
• Newborns from infected mothers are at risk.

Clinical Manifestations of HSV

• Encephalitis
• Keratitis
• Mucocutaneous disease (in immunocompromised hosts)
• Primary HSV-1 oropharyngeal herpes
• Recurrent labialis
• Primary genital herpes (HIV-2 or HSV-1)
• Recurrent herpes genitalis
• Neonatal herpes
• Genital tract

Clinical Manifestations of Primary Infection HSV 1

• Asymptomatic
• Pharyngitis, gingivostomatitis, follicular conjunctivitis, dendritic keratitis, blepharitis
• Most common in children under 5 in daycare centers/schools
• Incubation period of 2 to 12 days
• Resolved in 10-14 days
• Fever, inability to swallow, LAD
• Lip lesions are mostly recurrent lesions.
• Recurrence can last a lifetime
• No sequelae

Primary Genital Infection

• Severe multiple genital ulcers, pain, itching, dysuria, vaginal or urethral discharge, and tender inguinal LAD
• Lesions last 2-3 weeks.
• Viral shedding lasts 10-12 days.
• Constitutional symptoms: fever, myalgias, HA, aseptic meningitis, and urinary retention
• Cervicitis, proctitis
• Primary HSV-2 infection: no antibodies detected because they take while to develop
• Non-primary HSV infection: presence of pre-existing antibodies

Recurrent Disease

• The number of recurrences is increased during the first year.
• Lesions heal more rapidly
• Frequency of symptoms recurrences decreased from 4 to 5 recurrences during the first year
• It decreases to 3 to 4 in subsequent years
• HSV-2 Oro-labial recurrent infection are less common than with HSV-1 infection.
• Women have more recurrent episodes than men.
• Persons with prolonged symptoms with primary infection have more recurrent episodes.

Recurrent Infection

• Herpes labialis is HSV-1.
• Prodromal symptoms are common with HSV-1
• Lesion usually occurs on the vermilion border of the lip
• Progresses from vesicle to ulcer to crusted lesion
• Genital lesion appears on the labia majora, mons pubis, and buttocks.

Precipitating Factors for Recurrent Episodes

• UV light
• Fever
• Local trauma
• Trigeminal nerve manipulation
• Menstruation
• Emotional stress
• Immunosuppression
• Sexual intercourse

Diagnosis

• Send scraping of lesions for testing.
• Viral culture is less sensitive than PCR but more specific.
• PCR-NAAT is the preferred test.
• PCR of CSF for encephalitis
• Type-specific serology (ELISA/Western Blot), although serology might not be positive in the acute phase
• Cytologic exam via Tzank smear, but it has low sensitivity and cannot differentiate HSV1 from HSV 2

Tzank Test

• Detects Multinucleated Giant Cells
• They are not specific for HSV-1 or HSV-2

Complications of HSV

• Aseptic Meningitis cause by HSV-2
• Encephalitis cause by HSV-1
• Neonatal infection
• Immunocompromised Host (HIV & transplant)

Herpes Simplex Encephalitis (HSE)

• It is a life-threatening complication of HSV-1.
• Untreated cases MR > 80% of people die
• There are approximately 2,000 cases per year.
• It occurs with either primary or recurrent infection.
• It occurs in all ages, sexes, and seasons.
• Affects the temporal lobe, causing necrotizing hemorrhagic encephalitis.
• Symptoms include focal seizures, olfactory hallucinations, and bizarre behavior.

Herpes Simplex Encephalitis: Detection

• Electroencephalography: Sensitivity of ~84%
• Periodic lateralizing epileptiform discharges (PLEDs)
• Neuroimaging:
  • Computed tomography (lesions in 50-75% of patients)
  • Magnetic resonance imaging (>90% of cases)
• Brain biopsy:
  • Inflammation with widespread hemorrhagic necrosis
  • Intranuclear inclusions (50% of patients)
  • Reserved for patients not responding to acyclovir therapy

Manifestations and Outcomes of Neonatal Herpes

• Intrauterine Infection (5%) (transplacental or ascending)
• Intrapartum Infection (85%)
• Postnatal Infection (10%)
• Potential Outcomes: Viremia = Disseminated Disease (25%), Superficial (Skin, Eye, and/or Mouth) (45%), Neuronal Spread = Localized Encephalitis (30%)

Neonatal Infection

• Primary infection late in pregnancy creates the highest risk (30-50%).
• There is a high risk with shedding of HSV-1.
• If genital lesions are detected, the infant should be delivered by cesarean section.
• The mortality rate is very high.
• The situation is worse if the mother has a primary HSV infection during her last trimester of pregnancy or close to giving birth.

HSV in the Immunocompromised Host

• Recurrences are more severe and prolonged.
• Infection presents in unusual sites.
• Post-transplantation symptoms: tracheobronchitis, pneumonitis, esophagitis, and hepatitis
• AIDS symptoms: perianal ulcers, colitis, esophagitis, and acute retinal necrosis

Erythema Multiforme

• 75% of cases are preceded by an attack of HSV.
• HSV-1 or HSV-2
• Immune-mediated
• May recur

Treatment for HSV

• Acyclovir (ACV) Nucleoside analogue.
• Requires tri-PO4 by virally-encoded cellular kinase to inhibit HSV
• Inhibits HSV DNA polymerase

Genital HSV Infection: Recommended Treatments

• ACV, FCV, VCV can be used as treatment
• The treatments differ based on dose, and how often it should be taken
• The kind of treatment and drugs used vary for First Episode; Recurrent Symptomatic Episode; Daily Suppressive therapy; Treatment of episodic & Daily Suppressive in HSV/HIV

Additional treatments of HSV

• In immunocompromised host ACV is used to treat & suppress
• ACV-resistant strains in HIV-infected individuals (Foscarnet)
• Mutants due to lack of TK or altered substrate

Treatment by Condition

• Encephalitis (IV): ACV 10 mg/kg IV q 8 hr X 21 days
• Meningitis, Bell's palsy: No controlled trials, Oral ACV 200 mg 5X/d
• Neonatal herpes: IV ACV decreases mortality

Prevention of HSV

• Use of latex condoms
• Contact Isolation
• Use of gloves
• Use of sunscreen
• Cesarean section if active genital disease before rupture of membranes