Herpes Simplex Viruses

College of Medicine Microbiology
Medical Virology
DNA viruses( Herpesviruses): Dr.Jawad Kadhim Tarrad
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Important points about DNA viruses:
• Medically important DNA viruses comprise six families and share similar properties of nucleic acid composition, shape, and site of replication.
The families include: Herpesviridae, Hepadnaviridae, Poxviridae, Adenoviridae, Parvoviridae and Papovaviridae.
• Most DNA viruses contain dsDNA genomes(except parvoviridae family have ssDNA genome).
• DNA viruses have icosahedral symmetry (except poxviruses have complex symmetry).
• Herpes viruses, pox viruses and Hepadnaviruses are enveloped, whereas others are non-enveloped.
• They replicate in nucleus of infected cell (except poxviruses replicate in cytoplasm).

Herpesviruses:
• The herpes viruses family contains more than 100 viruses , only eight viruses are pathogens for human :
1. Herpes simplex virus type-1 (HSV-1).
2. Herpes simplex virus type-2 (HSV-2).
3. Varicella-Zoster virus (VZV).
4. Epstein-Barr virus (EBV).
5. Cytomegalovirus (CMV) .
6. Human herpes virus type-6(HHV-6).
7. Human herpes virus type-7(HHV-7).
8. Human herpes virus type-8(HHV-8).
• All herpes viruses are characterized by establish latent infection for lifelong.
• All herpes viruses are similar in structure( they have dsDNA, icosahedral and envelope with spikes).
• The herpes viruses are large size(120-200nm in diameter), second in size to poxviruses(300nm).





Herpes simplex virus(HSV):
• It has two serotypes; HSV-1 and HSV-2.
Important properties:
• They belong to Herpesviridae family:
• They have dsDNA.
• Nucleocapsid is icosahedral symmetry.
• Enveloped with spikes.
Source and transmission:
• Humans are natural hosts.
• HSV-1 is transmitted via respiratory secretions and saliva(through kissing) or by direct contact.
• HSV-2 is transmitted by sexual contact and perinatally.
Replication:
• HSVs invade epithelial cells by attached to cellular receptor, and then enter by fusion within cell membrane. After uncoating, the viral genome moves to nucleus for replication. Assembly processes occur in nucleus. The progeny viruses acquire their envelopes from nuclear membrane of infected cell. After completion, the new viruses release from infected cells by exocytosis.
• Growth cycle of HSVs proceed rapidly, requiring 8-16 hours for completion.
Pathogenesis:
• Both serotypes of herpes simplex viruses cause two types of clinical disease :
1- Primary infection.
2- Recurrent infection.
• In primary infection, the virus replicates initially in epithelial cells of skin and/or mucous membrane at initial site of infection(HSV-1 replicates in cells of mouth or on face, whereas HSV-2 in cells of genital area). After incubation period(I.P): 5-8 days , typical lesion is skin vesicle that contain serous fluid filled with virus, when the vesicle rupture , virus is liberated and can be transmitted to other individuals.
• Both serotypes are similar in structure, but differ in antigenicity and in location of lesions.
o The diseases caused by HSV-1 are ,in general , above the waist 85% (especially in facial area), whereas those caused by HSV-2 are below waist 85% (especially in genital area).
o HSV-1 causes acute gingivostomatitis, herpes labialis(cold sore), keratoconjunctivitis and encephalitis. While HSV-2 causes genital herpes, neonatal herpes ,and aseptic meningitis.
• In recurrent infection, the virus has ability to cause latent infections in nerve cells. The virus migrates up the neuron and become latent in dorsal sensory ganglion cell (HSV-1 latent in trigeminal (cranial) ganglia, whereas HSV-2 latent in lumbar and sacral ganglia).
• The latent virus can be reactivated and cause recurrent infection by variety inducers (risk factors), eg: sun light, hormonal changes , trauma, stress and fever, at which time it migrates down the neuron and replicates in skin or mucous, causing recurrent lesions.
Diseases and clinical findings:
• Gingivostomatitis: occurs primarily in children and is characterized by multiple painful vesicular lesions in the mouth( in mucous membrane and gum).Fever and irritability are common with infection . Many children have asymptomatic primary infection. The lesions heal spontaneously in 2-3 weeks. Primary infection is more severe than recurrence.
• Herpes labialis (fever blister or cold sore): recurrent form and is characterized by crops of vesicles, usually at mucocutaneous junction of lips or nose. The cluster of vesicles is painful. It is healing in 8-10days. Also it cause herpetic whitlow(hand herpes).
• Keratoconjunctivitis: HSV-1 infection of eye may occur .The disease is characterized by corneal ulcers and lesions of conjunctival epithelium. Recurrences can lead to scarring and blindness.
• Herpes encephalitis : is characterized by a necrotic lesion in one temporal lobe of brain. Fever ,headache , vomiting, seizures, and mental status are typical features.
• Herpes genitalis(STD): is characterized by painful vesicular lesions and ulcerative lesions on genitals and anal area(penis, cervix, vagina, vulva, perineum). Primary infections are associated with fever ,dysuria, inguinal adenopathy and malaise lasting 1-2 week . The lesions are more severe in primary than in recurrent.
• Neonatal herpes: the infection originates from contact with vesicular lesions within birth canal (during delivery) or acquired after birth from carriers handling the child. The infection varies from severe(encephalitis) or mild (skin infection) to asymptomatic. Serious infection is more likely to occur in mother with primary than in secondary for two reasons(i) Amount of virus producing during primary infection is greater than during secondary (ii)Mother who have been previously infection can pass IgG across placenta , which can protect neonate from infection.
• Aseptic meningitis ; caused by HSV-2 is usually mild with few sequelae. Infection of meninges cells occurs, with cell death and brain tissue swelling.
Epidemiology:
• Herpes viruses cause wide distribution of infections. The infections are extremely widespread in human population.
• Human only host, there are no animal reservoirs. Infected persons with HSV are remain source of infection for lifelong.
• HSV-1 infections are common in young children, while HSV-2 infections are common in young adults.
Lab. Dx:
• HSV can be detected from skin lesions by electronic microscope. Multinucleated giant cells detected cytologically in smear of scrapings of lesions suggest herpes infection.
• Serologic tests are not very useful because high prevalence of antibody in normal population.
• HSV DNA can be detected by PCR .
Control:
• Treatment: Acyclovir is drug of choice for HSV infections. Foscarnet is used in cases of acyclovir-resistant HSV infections .The drugs have no effect on the latent state.
• Prevention:
1. Avoiding contact with vesicular lesion or ulcer.
2. To avoid infection of fetus during delivery, Cesarean section is recommended for women are at term and who have genital lesion or positive viral cultures. Barrier contraceptives and safe sex are important preventive measures
3. There is no vaccine available to prevent HSV infections.



Varicella-Zoster virus(VZV):
Source and transmission:
• Humans are natural hosts.
• VZV is highly contagious and transmitted by
1. Respiratory secretions.
2. Direct contact.
Pathogenesis:
• VZV initially infects epithelial cells of mucosa layer of upper respiratory tract , spreads to and multiplies in lymph nodes, enters the bloodstream (primary viremia) and spreads to the liver and spleen, and then disseminated (secondary viremia)back to the respiratory tract(mucous membrane) and skin , where the vesicular rash occurs.
• VZV spreads to innervating neurons and is transported to dorsal ganglia to establish the latent state in sensory neuron. Reactivation of latency can be triggered by increasing age and immunocompromise due to cancer and AIDS , or immunosuppressive therapy for organ transplantation or cancer. Reactivation results in virus travel down the axon with recurrent infection of epithelial cells innervated by sensory nerve and resultant vesicular lesions on skin , usually involving a dermatome(shingle).
Diseases and clinical features :
• Primary infection of VZV is called varicella infection(chickenpox) , highly contagious disease, it usually occurs in children .The infection has incubation period of 10-20 days followed by prodrome symptoms : fever, malaise, itch (pruritus) and then generalized vesicular rash that progresses to macules, pustules and scabs(chickenpox) . The rash lasting 5-7 days. The lesions generally begin on the head and face and progress to trunk and extremities.
• Recurrent form is called zoster infection(shingles) , sporadic disease, usually occur in adults and immunocompromised individuals. Reactivation of latent VZV is characterized by unilateral, localized , painful, vesicular rash in skin of chest along dermatome innervated by particular sensory ganglia.
• Complications of varicella infection include; varicella pneumonia, varicella encephalitis, and bacterial superinfection of skin. Maternal infection during pregnancy can cause congenital varicella syndrome characterized by birth defects. Whereas most complication of herpes zoster is neuralgia.
• Previous infection with varicella is believed to confer lifelong immunity.

Epidemiology:
• VZV infections are occurring worldwide distribution.
• Humans are natural hosts for the virus.
• Most cases of VZV occur in children.
• Varicella infections are much more common in winter and spring than in summer in temperate climates.
Lab. Dx :
• VZV can be detected by electron microscope . Multinucleated giant cells detected cytologically in smear of scrapings of lesions.
• VZV can be isolated in cell culture.
• Serological tests: VZV can be identified with specific fluorescent antibody staining.
Control :
• Treatment: Acyclovir is used to treat varicella and zoster infection. If VZV resistant to acyclovir is treated with foscarnet.
• Prevention :
1. Attenuated VZV vaccine is effective in preventing infection (provide protection for 20 years), but the vaccine does not eliminate the latent state. Because it is live vaccine, it should not be given to immunocompromised patients or to pregnant women.
2. Isolation of hospitalized patients is critical to prevention of nosocomial spread.