Genital Herpes Study Notes

Genital Herpes

Overview of Herpesviruses

• Over 100 herpesviruses have been identified that infect a variety of species including mammals, birds, reptiles, and even oysters.

Definitions and Characteristics

• Herpesvirus: Derived from Greek word "herpein" meaning to creep, which refers to the spreading of lesions.

• Distinctive Characteristic: Herpesviruses can enter a latent state within the host, becoming dormant after the initial infection. They have the capability to be reactivated months or years later, leading to recurrent infections and associated diseases. This phenomenon underscores the clinical significance of herpesviruses.

Structure of Herpesviruses

• Key components of herpesviruses include:

  • Envelope Proteins: gB - gN

  • Tegument: Layer between the envelope and the nucleocapsid

  • DNA: Genetic material of the virus

  • Nucleocapsid: Capsid containing the viral genome

  • Lipid Envelope: Outer layer derived from the host cell membrane.

  • Reference: Principles of Virology, 2nd Ed, SL Flint, LW Enquist, VR Racaniello, AM Skalka, Eds, ASM Press

Herpesviridae Family and Sub-Family

• Human Herpesvirus Types:

  • Herpes Simplex Virus Type 1 (HSV-1):

  • Causes recurrent oral disease (fever blister, cold sore)

  • Herpes Simplex Virus Type 2 (HSV-2):

  • Causes recurrent genital disease (genital herpes)

  • Varicella-Zoster Virus:

  • Causes chickenpox & shingles

  • Cytomegalovirus:

  • Associated with congenital defects and opportunistic diseases in AIDS patients

  • Human Herpesvirus 6:

  • Causes roseola

  • Human Herpesvirus 7:

  • Causes roseola

  • Epstein-Barr Virus:

  • Causes infectious mononucleosis

  • Human Herpesvirus 8:

  • Associated with Kaposi’s sarcoma (AIDS)

Blood-Borne Human Herpesviruses

• Non-Alpha Herpesviruses:

  • Cytomegalovirus

  • Epstein-Barr Virus

  • Human Herpesvirus Types 6, 7, and 8

• These viruses establish lifelong latent infections within circulating lymphocytes, often residing in bone marrow cells.

Neurotropic Human Herpesviruses

• Types Included:

  • Herpes Simplex Virus Type 1 (HSV-1)

  • Herpes Simplex Virus Type 2 (HSV-2)

  • Varicella-Zoster Virus

• Latent Locations: These viruses establish lifelong infections in sensory ganglia neurons.

Transmission of Herpes Simplex Virus Infections

• Transmission most frequently occurs through close contact with an infected person shedding the virus from mucosal surfaces.

• The transmission occurs through inoculation of the virus onto susceptible mucosal surfaces or through small cracks in the skin.

Epidemiology of Herpes Simplex Viruses

• HSV-1:

  • 3.8 billion individuals worldwide under the age of 50 have HSV-1 infection.

  • Approximately 200 million individuals in the U.S. under the age of 50.

• HSV-2:

  • An estimated 1 in 6 individuals in the U.S. aged 15–49 are infected with HSV-2.

Primary Infection Manifestations of Herpes Simplex Virus Type 1

• Common results of primary HSV-1 infection:

  • Gingivostomatitis: 90% (often symptomless)

  • Minor Illness: 9%

  • Diseases include:

  • Keratitis: 1% disease occurrence

  • Gingivostomatitis

  • Genital herpes

  • Eczema herpeticum

  • Encephalitis

  • Disseminated herpes

  • Whitlow

  • Herpes gladiatorum

Stages of Herpes Simplex Virus Type 1

1. Primary Infection

2. Latent Phase

3. Recurrence

• Latency and reactivation dynamics are crucial for understanding HSV infections.

Latency of Herpes Simplex Virus Type 1

• Location of Latency: Virus DNA detected in human trigeminal ganglia.

• Neurons of sensory ganglia serve as the primary or exclusive site of latency.

• Virus Genome Configuration: The latent virus genome exists extrachromosomally, possibly in a circular form, with multiple copies per neuron (more than ~25% of neurons harbor latent virus).

• Quantity in Neurons: Approximately ~6,000 neurons in trigeminal ganglia may carry the latent virus.

Latency-Associated Transcript (LAT)

• Defined as a virus-encoded mRNA that accumulates in the nuclei of neurons containing latent virus.

• The functions of LAT remain controversial; however, it is believed to downregulate apoptosis, therefore preventing programmed cell death of neurons.

• LAT serves as a marker for HSV-1 and HSV-2 latency.

Reactivation from Latent State

• Triggers for reactivation include:

  • Local stimuli (e.g., tissue injury)

  • Systemic conditions (e.g., fever, stress, sunlight)

• Importantly, reactivation is not associated with the destruction of neurons in the sensory ganglia.

Recurrent Disease Associated with Herpes Simplex Virus Type 1

• Manifestations of Recurrence:

  • Oral disease: fever blisters/cold sores.

  • Ocular disease: stromal keratitis.

  • Extremities: Whitlow (finger infections).

• Vesicles resulting from HSV-1 infection:

  • Appearance: Blister-like lesions with a high viral load in vesicular fluid; lesions eventually crust over and heal.

Herpes Simplex Encephalitis

• Severity: Among the most severe viral infections of the brain.

• Mortality Rate: Exceeds 70%, with death occurring approximately 10 days post-symptoms onset.

• Survivors often suffer severe neurological deficits following infection.

• The virus preferentially affects the temporal lobes in immunologically normal adults.

Herpes Simplex Virus Type 2 (Genital Herpes)

• Understanding HSV-2 and differential characteristics from HSV-1 is crucial:

  • Genetic, immunological, and clinical differences exist between HSV-1 and HSV-2.

• Predominant Etiological Agent:

  • HSV-2 is recognized as the primary cause of genital herpes, although HSV-1 can also lead to genital outbreaks.

Historical Perspectives on Genital Herpes

• Diday & Doyon (1886): Authored "Les herpes genitaux," the inaugural book on genital herpes.

• They noted that genital herpes often follows venereal infections (e.g., syphilis, gonorrhea), albeit not all individuals with venereal diseases developed genital herpes. Furthermore, they described that eruptions often reoccur after menstruation, attributing this pattern to a "trigger mechanism" of the nervous system.

Primary Infection Features of Herpes Simplex Virus Type 2

• Incubation Period: Ranges from 6–8 days, with a maximum of 14 days.

• Prominent Symptoms: Development of numerous painful vesicles of long duration; lesions crust over approximately 20 days post-initial appearance.

Complications of Primary Genital Herpes Infections

• Meningitis Incidence: About 28% of the cases.

• Autoinoculation Rate: Approximately 21%.

Latency of Herpes Simplex Virus Type 2

• Similar to HSV-1, HSV-2's latent virus DNA is detected in human sacral ganglia, with non-integrated extrachromosomal virus genomes in neurons.

Reactivation Dynamics for Herpes Simplex Virus Type 2

• Similar reactivation triggers exist as with HSV-1, including local tissue injury and systemic factors like fever and stress. Importantly, reactivation does not destroy neurons.

Recurrent Genital Herpes with Herpes Simplex Virus Type 2

• Symptoms Upon Recurrence: Patients may experience prodromal symptoms before vesicle development. Vesicles tend to be unilateral, localized, fewer in number, less painful, and heal in about 12 days.

• Asymptomatic shedding of infectious virus correlates with recurrent HSV-2 genital disease, challenging earlier beliefs that vesicle presence was essential for virus transmission.

Changing Understanding of Asymptomatic Shedding

• Original Assumption: Patients without vesicles do not shed the virus. This has been disproven by clinical data showing 55% of women experienced asymptomatic shedding.

• Recent findings reveal that asymptomatic virus shedding occurs nearly constantly, typically every 6-12 hours, controlled by innate immunity, which, in most cases, prevents clinical disease. Chronic inflammation of the genital mucosa continues to occur in patients taking antiviral therapy.

Neonatal Infection Associated with Herpes Simplex Virus Type 2

• Incidence: Approximately 1 in 3,000 to 1 in 5,000 deliveries annually.

• Influential Factors for Virus Transmission:

  • Primary maternal infection (30-50% risk) compared to recurrent maternal infection (3% risk).

  • Mother's antibody status.

• Clinical Manifestations: May lead to skin vesicles or scarring, corneal disease, viral dissemination, and high mortality rates (exceed 80%) without antiviral treatment.

Antiviral Management of Herpes Simplex Infections

• Acyclovir (Valacyclovir): Antiviral agent of choice for treating both HSV-1 and HSV-2 infections.

  • Exhibits a high therapeutic index and low toxicity.

  • Mechanism of action relies on the virus-encoded thymidine kinase enzyme.

• Phosphorylation Process:

  1. Acyclovir is preferentially phosphorylated in HSV or VZV infected cells, resulting in acyclovir monophosphate.

  2. Further phosphorylation by cellular kinases converts it to acyclovir diphosphate, then to acyclovir triphosphate, which effectively blocks viral DNA replication via inhibition of viral DNA polymerase.

• Valacyclovir (Valtrex): A second-generation acyclovir with an added valine side chain.

  • Significantly higher oral bioavailability than acyclovir and undergoes conversion to acyclovir within cells.

  • Mechanism of action identical to that of acyclovir.

Vaccination Status

• No vaccine is currently available to prevent infections caused by either herpes simplex virus type 1 or type 2, including genital herpes.