Human Herpes Viruses

1. Human Herpes Viruses Latent Viruses

2. Introduction • Herpes Viruses are a leading cause of human viral diseases, second only to influenza and cold viruses. • Are capable of causing overt disease or remaining silent for many years only to be reactivated. • Name Herpes comes from the Latin herpes which, in turn, comes from the Greek word herpein which means to creep.

3. Characteristics of HSV • DNA double stranded virus, linear • 125-250 Kb long, relatively big • Enveloped • Virion size 200 nm, relatively big • 9 HSVs, Ex. Varicella, EBV, CMV • Diseases: Chickenbox, Mononucleosis, Hepatitis, Encephalitis • Recurrent eye, mouth and genital lesions Chickenpox, Varicella Zoster

4. Classification • There are 25 families in the Herpeotoviridae but only 6 of them infect man with any regularity. Herpes Simplex virus Type 1 (HSV-1) Herpes Simplex virus Type 2 (HSV-2) Epstein Barr virus (EBV) Cytomegalovirus (CMV) Varicella Zoster virus (VZV) Human Herpes virus 6 Human Herpes virus 8

5. Herpes Simplex Virus (HSV) • These are very large viruses and their genome encodes at least 80 proteins. • Half are not directly involved in the virus structure. • Almost any human cell type can be affected by HSV.

7. Epidemiology • HSV-1 and 2 infections are life-long. • The virus is found in the lesions on the skin but can be present in body fluids including saliva and vaginal secretions. • As a result of poor hygiene in underdeveloped countries, HSV-1 antibodies are found in more than 90% of children.

8. Epidemiology 2 • HSV-2 is normally spread sexually and is found in the anus, rectum and upper alimentary tract as well as the genital area. • An infant can be infected at birth by a genitally-infected mother. • The infant can also be infected in utero if the mother’s infection spreads. • Because of the infant’s underdeveloped immune system, the resulting infection can be very severe and sometimes be deadly.

9. Disease caused by Herpes Simplex Viruses • Oral Herpes - Cold sores • Herpetic gingiovostomatitis, the infection, often initially on the lips spreads to all parts of the mouth and pharynx.

10. Herpes Virus and Common Diseases • Everybody knows chickenpox and likely you experienced the disease as a child, can be dangerous when exposed to it in adulthood • Another common ailment is lip and mouth “cold sores” • Genital Herpes lesions caused by HSV, sexually transmitted • HSV-1 cold sores (mild but annoying diseases) • HSV-2 genital herpes • Varicella zoster: chickenpox • However the Herpes family is huge, over 100 members HSV-1 Cold sore HSV-2 Genital Herpes

11. Disease caused by Herpes Simplex Viruses • Eczema Herpeticum • This is found in children with active eczema. • The virus can spread to other organs such as the liver and adrenals.

12. Disease caused by Herpes Simplex Viruses • Genital Herpes • Is usually the result of HSV-2. • Primary infection is often asymptomatic but many painful lesions can be developed on the shaft of the penis and vulva, vagina, cervix and perianal region of women.

13. Genital Herpes

14. Genital Herpes • In both sexes, the urethra can be involved. • Genital Herpes infections can be accompanied by a variety of symptoms including fever, myalgia, glandular inflammation of the groin area (inguinal). • Some patients have only infrequent recurrences but others experience recurrences as often as every 14-21 days.

15. HSV Establishes Latent Infections • Once infection has taken place HSV can remain dormant for months, years, lifetime • Cell types that HSV can infect and remain dormant • Neurons, B-cells and T-cells • Examples: • Shingles which can appear years after first chickepox infection (caused by varicella zoster, causes both chickenpox and shingles) • Genital Herpes outbreaks

16. HSV Capsid • Enclosed in an envelope • Capsid has icosahedral structure • Capsid is bilayered • Constructed from 6 proteins • VP5 is the main one • Envelope contains at least 10 different glycoproteins gB-gM • Envelope also contains non-glycosylated proteins

17. HSV Entry Into Host Occurs Via Heparan Sulfate Proteoglycans • gB and gC bind to host glycoproteins with heparan sulfate moieties (repeating dissacharide: glucoronic and n-acetyl glucosamine) • Following gB and gC is gD which binds to nectin1D • OR HVEM (herpes virus entry mediator) • Fusion occurs between viral envelope and host membrane • Nucleocapsid is released into cytosol OR in acidified endosomes • Transport to nuclear envelope occurs via T and capsid interaction • DNA is released into nucleus • Capsid disintegrates http://www.dipartimentobiologia.it/doctoraltraining/campadelli.htm

18. Envelopment and Egress: 3 Possible Routes

19. Diagnosis of HSV Infections • Cells may be obtained from the base of the lesion (called a Tzank smear) and histochemistry performed. • These can be seen in the smears as multinucleated giant cells and contain Cowdry type A inclusion bodies.

20. Diagnosis of HSV Infections

21. Diagnosis of HSV Infections • The cells can also be stained with specific antibodies in an immunofluorescence test. • It can also be detected by viral DNA by in situ hybridization. • Type-specific antibodies can distinguish between HSV-1 and HSV-2.

22. Treatment • Acyclovir • A Safe and extremely well-tolerated drug. • More than 35 million patients have been consistent and reassuring. • Some authorities have proposed making acyclovir available as a non-prescription drug. • Adverse effects, usually mild, include nausea, vomiting, rash and headache.

23. Treatment • Valacyclovir • New antiviral agent • Is the 1-valine ester prodrug of acyclovir. • It has an oral bioavailability three to five times greater than that of acyclovir. • Several large trials have shown that it is safe and well tolerated.

24. Treatment • Famciclovir • Another new antiviral medication • Is the oral form of penciclovir, a purine analog similar to acyclovir. • Oral bioavailability is 77% and the drug is quickly converted to its active form. • Famciclovir’s intracellular half-life is 10 times longer than acyclovir’s. • Dosing less frequently than twice daily is not recommended.