Herpse Viruses

1. Herpse Viruses Xiao-Kui GUO Dept. of Microbiology and Parasitology

2. BIOLOGICAL PROPERTIES

3. Structure & Composition • Size: 150-200nm. • Enveloped double stranded DNA viruses. • Capsid: icosahedral symmetry and has 162 capsomeres. • Nucleocapsid surrounded by an envelope contains viral glycoprotein spikes about 8 nm long. • Genome: Large and encodes at least 100 different proteins.

4. Classification

5. Herpesvirus Replication

6. Herpes Simplex Viruses

7. Properties • Belong to the alphaherpesvirus subfamily of herpesviruses • Double stranded DNA enveloped virus with a genome of around 150 kb • The genome of HSV-1 and HSV-2 share 50 - 70% homology. • They also share several cross-reactive epitopes with each other. There is also antigenic cross-reaction with VZV. • Man is the only natural host for HSV.

8. Epidemiology (1) • HSV is spread by contact, as the virus is shed in saliva, tears, genital and other secretions. • By far the most common form of infection results from a kiss given to a child or adult from a person shedding the virus. • Primary infection is usually trivial or subclinical in most individuals. It is a disease mainly of very young children ie. those below 5 years. • There are 2 peaks of incidence, the first at 0 - 5 years and the second in the late teens, when sexual activity commences. • About 10% of the population acquires HSV infection through the genital route and the risk is concentrated in young adulthood.

9. Epidemiology (2) • Generally HSV-1 causes infection above the belt and HSV-2 below the belt. In fact, 40% of clinical isolates from genital sores are HSV-1, and 5% of strains isolated from the facial area are HSV-2. This data is complicated by oral sexual practices. • Following primary infection, 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences. • The actual frequency of recurrences varies widely between individuals. The mean number of episodes per year is about 1.6.

10. Epidemiology • Worldwide in distribution. • No animal reservoirs or vectors. • Transmission is by contact with infected secretions. • The epidemiology of type 1 and type 2 herpes simplex virus differs.

11. Pathogenesis • During the primary infection, HSV spreads locally and a short-lived viraemia occurs, whereby the virus is disseminated in the body. Spread to the to craniospinal ganglia occurs. • The virus then establishes latency in the craniospinal ganglia. • The exact mechanism of latency is not known, it may be true latency where there is no viral replication or viral persistence where there is a low level of viral replication. • Reactivation- It is well known that many triggers can provoke a recurrence. These include physical or psychological stress, infection; especially pneumococcal and meningococcal, fever, irradiation; including sunlight, and menstruation.

14. Immunity • Transplacentally (经胎盘的) acquired antibodies. • HSV-1 antibodies－ Appear in early childhood. • HSV-2 antibodies－Rise during the age of adolescence and sexual activity. • Primary infections－IgM antibodies appear transiently and are followed by IgG and IgA antibodies that persist for long periods. • Latent state－ Antibodies can modify subsequent disease.

15. Clinical Manifestations HSV is involved in a variety of clinical manifestations which includes ;- 1. Acute gingivostomatitis龈口炎 2. Herpes Labialis (cold sore) 3. Ocular Herpes 4. Herpes Genitalis 5. Other forms of cutaneous herpes 7. Meningitis 8. Encephalitis 9. Neonatal herpes

17. Oral-facial Herpes • Acute Gingivostomatitis • Acute gingivostomatitis is the commonest manifestation of primary herpetic infection. • The patient experiences pain and bleeding of the gums. 1 - 8 mm ulcers with necrotic bases are present. Neck glands are commonly enlarged accompanied by fever. • Usually a self limiting disease which lasts around 13 days. • Herpes labialis (cold sore) • Following primary infection, 45% of orally infected individuals will experience reactivation. The actual frequency of recurrences varies widely between individuals. • Herpes labialis (cold sore) is a recurrence of oral HSV. • A prodrome of tingling, warmth or itching at the site usually heralds the recurrence. About 12 hours later, red­ness appears followed by papules and then vesicles.

19. Ocular Herpes HSV causes a broad spectrum of ocular disease, ranging from mild superficial lesions involving the external eye, to severe sight-threatening diseases of the inner eye. Diseases caused include the following:- • Primary HSV keratitis – dendritic ulcers • Recurrent HSV keratitis • HSV conjunctivitis • Iridocyclitis, chorioretinitis and cataract

20. Genital Herpes • Genital lesions may be primary, recurrent or initial. • Many sites can be involved which includes the penis, vagina, cervix, anus, vulva, bladder, the sacral nerve routes, the spinal and the meninges. The lesions of genital herpes are particularly prone to secondary bacterial infection eg. S.aureus, Streptococcus, Trichomonas and Candida Albicans. • Dysuria is a common complaint, in severe cases, there may be urinary retention. • Local sensory nerves may be involved leading to the development of a radiculitis. A mild meningitis may be present. • 60% of patients with genital herpes will experience recurrences. Recurrent lesions in the perianal area tend to be more numerous and persists longer than their oral HSV-1 counterparts.

21. Genital herpes.

22. Herpes Simplex Encephalitis • Herpes Simplex encephalitis is one of the most serious complications of herpes simplex disease. There are two forms: • Neonatal – there is global involvement and the brain is almost liquefied. The mortality rate approaches 100%. • Focal disease – the temporal lobe is most commonly affected. This form of the disease appears in children and adults. It is possible that many of these cases arise from reactivation of virus. The mortality rate is high (70%) without treatment. • It is of utmost importance to make a diagnosis of HSE early. It is general practice that IV acyclovir is given in all cases of suspected HSE before laboratory results are available.

23. Neonatal Herpes Simplex (1) • Incidence of neonatal HSV infection varies inexplicably from country to country e.g. from 1 in 4000 live births in the U.S. to 1 in 10000 live births in the UK • The baby is usually infected perinatally during passage through the birth canal. • Premature rupturing of the membranes is a well recognized risk factor. • The risk of perinatal transmission is greatest when there is a florid primary infection in the mother. • There is an appreciably smaller risk from recurrent lesions in the mother, probably because of the lower viral load and the presence of specific antibody • The baby may also be infected from other sources such as oral lesions from the mother or a herpetic whitlow in a nurse.

24. Neonatal Herpes Simplex (2) • The spectrum of neonatal HSV infection varies from a mild disease localized to the skin to a fatal disseminated infection. • Infection is particularly dangerous in premature infants. • Where dissemination occurs, the organs most commonly involved are the liver, adrenals and the brain. • Where the brain is involved, the prognosis is particularly severe. The encephalitis is global and of such severity that the brain may be liquefied. • A large proportion of survivors of neonatal HSV infection have residual disabilities. • Acyclovir should be promptly given in all suspected cases of neonatal HSV infection. • The only means of prevention is to offer caesarean section to mothers with florid genital HSV lesions.

25. Other Manifestations • Disseminated herpes simplex are much more likely to occur in immunocompromised individuals. The widespread vesicular resembles that of chickenpox. Many organs other than the skin may be involved e.g. liver, spleen, lungs, and CNS. • Other cutaneous manifestations include • eczema herpeticum which is potentially a serious disease that occurs in patients with eczema. • Herpetic whitlow which arise from implantation of the virus into the skin and typically affect the fingers. • “zosteriform herpes simplex". This is a rare presentation of herpes simplex where HSV lesions appear in a dermatomal distribution similar to herpes zoster.

26. Laboratory Diagnosis • Direct Detection • Electron microscopy of vesicle fluid - rapid result but cannot distinguish between HSV and VZV • Immunofluorescence of skin scrappings - can distinguish between HSV and VZV • PCR - now used routinely for the diagnosis of herpes simple encephalitis • Virus Isolation • HSV-1 and HSV-2 are among the easiest viruses to cultivate. It usually takes only 1 - 5 days for a result to be available. • Serology • Not that useful in the acute phase because it takes 1-2 weeks for before antibodies appear after infection. Used to document to recent infection.

27. Cytopathic Effect of HSV in cell culture: Note the ballooning of cells. (Linda Stannard, University of Cape Town, S.A.) Positive immunofluorescence test for HSV antigen in epithelial cell. (Virology Laboratory, New-Yale Haven Hospital)

28. Management At present, there are only a few indications of antiviral chemo­therapy, with the high cost of antiviral drugs being a main consideration. Generally, antiviral chemotherapy is indicated where the primary infection is especially severe, where there is dissemination, where sight is threatened, and herpes simplex encephalitis. Acyclovir阿昔洛维– this the drug of choice for most situations at present. It is available in a number of formulations:- • I.V. (HSV infection in normal and immunocompromised patients) • Oral (treatment and long term suppression of mucocutaneous herpes and prophylaxis of HSV in immunocompromised patients) • Cream (HSV infection of the skin and mucous membranes) • Ophthalmic ointment Famciclovir and valacyclovir – oral only, more expensive than acyclovir. Other older agents – e.g. idoxuridine, trifluorothymidine, Vidarabine (ara-A). • These agents are highly toxic and is suitable for topical use for opthalmic infection only

29. Varicella-Zoster Virus

30. Biological Properties • Morphologically identical to herpes simplex virus. • Cause chickenpox and zoster. • Cross-protection between zoster and varicella.

31. Pathogenesis & Pathology • Varicella • The route of infection is the mucosa of the upper respiratory tract or the conjunctiva. • Primary viremia and secondary viremia • Zoster • Distribution of lesions in the skin corresponds closely to the areas of innervation (神经分布) from an individual dorsal root ganglion (脊神经根).

32. Pathogenesis

34. Clinical findings Rash of Chickenpox

35. Zoster

36. Immunity • Antibodies induced by varicella vaccine persist for at least 20 years. • Zoster occurs in the presence of neutralizing antibody to varicella.

37. Laboratory Diagnosis • Immunofluorescence staining. • Isolation and Identification of Virus. • Serology

38. Epidemiology • Varicella and zoster occur worldwide. • Varicella－A common epidemic disease of childhood. • Zoster－ sporadically, chiefly in adults.

39. Treatment & Prevention • Varicella: required no treatment in normal children. • Gamma globulin of high varicella-zoster virus antibody titer. • Several antiviral compounds. • Live attenuated (减毒活疫苗) varicella vaccine.

40. Cytomegalovirus

41. Biological Properties • The largest genetic content of the human herpesviruses. • ds DNA enveloped virus • Species-specific and cell type-specific. • Intranuclear inclusion body and multinucleated cells.

42. Pathogenesis & Pathology • Normal Hosts • Immunosuppressed Hosts • Congenital and Perinatal Infections

43. Pathogenesis of CMV infections

44. Immunity • Cytomegalovirus-specific IgM, IgA, and IgG antibodies. • Antibody in breast milk does not prevent transmission of infection to breast-feeding infants.

45. Laboratory Diagnosis • PCR and Antigen Detection Assays • Isolation of Virus • Serology

46. (Virology Laboratory, New-Yale Haven Hospital) CMV pp65 antigenaemia test

47. Epidemiology • Endemic in all parts of the world. • Transmission requires close person-to-person contact. Incidence of Cytomegalic Disease

48. Treatment & Control • Ganciclovir (丙氧鸟苷), foscarnet (鳞甲酸), and acyclovir. • Live and recombinant cytomegalovirus vaccines.

49. Epstein-Barr Virus

50. Biological Properties • Biology of EBV • Viral Antigens Latent phase antigens－EBNAsEBV (核抗原) －LMPs (潜伏感染膜蛋白) Early antigens －nonstructural proteins. Late antigens －viral capsid antigen (病毒衣壳抗原) and viral envelope. • Experimental Animal Infections.