Dr. Amanj Saeed MBCHB, MSc, PhD amanj.saeed@krg.org 5 Herpesviruses Dr. Amanj Saeed MBCHB, MSc, PhD amanj.saeed@krg.org

Herpesviruses herpes viruses are widely disseminated in nature eight human herpesviruses have been isolated: herpes simplex virus 1 and 2 varicella zoster virus human cytomegalovirus Epstein-Barr virus human herpesviruses 6 to 8

Herpesviruses: definition Spherical, 150-200 nm in diameter herpesviruses contain a linear, ds DNA genome, 125-240 kbp. More than 35 proteins in virion. the genome is packaged into a characteristic 162 capsomere nucleocapsid the capsid is then enclosed in a viral tegument and a lipid and glycoprotein envelope

Herpesvirus DNAs herpesvirus genomes vary greatly in size, base composition and structure genomes vary in length from 120 kb to 230 kb and contain different arrangements of unique and repeat sequences

Biological Properties Herpesviruses share three biological properties: all encode enzymes involved in viral replication production of infectious virus leads to destruction of the host cell all establish latent infection which persists for the lifetime of the host

Pathogenesis Cell entry Expression of viral genes Host responses

Pathogenesis Cell entry Expression of viral genes Host responses

Expression of viral genes Expression of viral genes occurs in a regulated cascade: immediate early genes: essential for co-ordinate regulation of other viral genes delayed early genes: encode proteins essential for viral DNA replication late genes: encode structural proteins

Pathogenesis Cell entry Expression of viral genes Host responses

Herpes simplex viruses Primary infection refer to the first infection with either HSV. Reactivation refer to production of infective virus by a latently infected cells.

Herpes simplex viruses Oropharyngeal infection Primary infection occur in infancy or early childhood. Occur as a result of close contact with an older person (kissing). It may be asymptomatic or present as acute gingivostomatitis. Form vesicles on gum and oral mucosa which eventually break down to form ulcers. Herpetic lesions affect anterior part of the mouth, involve lips and cirumoral skin.

Herpes simplex viruses Oropharyngeal infection Fever Difficulty in feeding. The time from onset to healing is about 2 weeks. In latter life recurrences manifest around the mouth (lip margin) as a cluster of vesicles heralded some hours previously by an itching sensation. Recurrences are milder, more localised, and shorter duration than primary infection. the lesion crust and heal within few days.

Herpes simplex viruses Dermal infection (Nurses, dentists, Wrestlers) Genital infection Ophthalmic infection Meningitis and encephalitis

Herpes simplex viruses Genital infection In children herpetic vulvovaginitis may indicate sexual abuse?? There is a reported relationship of HSV and cervical cancer.

Herpes Simplex infection

HSV infection in immuno-deficient cases Cause severe infection in immunodeficient patients. Common in patients whose cellular immunity impaired by malignant diseases or cytotoxic therapy. Common in AIDS patients.

Herpes simplex viruses Pathogenesis Reactivation of the virus may occur and could be triggered by: Cold exposure Febrile illness Sunlight Menstruation And therapeutic irradiation.

Diagnosis Lesion is characteristic. Diagnosis is necessary in eye and genital infection. Complement fixation. ELISA Virus can be isolated by inoculation of swabs into cell line and observe the characteristic cytopathic effect. Vigorous scrapping of the base of lesions reveal multinucleate cells containing intra-nuclear inclusions.

Diagnosis Electron microscopy Immunofluorescence PCR

Treatment Acyclovir (ACV) is the drug of choice. It is available as : oral, topical, and intravenous preparations. Normally primary and recurrent infection does not require treatment except immunodifficient patients. Eye infection can be treated by topical ACV. ACV in pregnancy is controversial, it can be given in late pregnancy to protect the baby from infection. Severe generalised infection in immunodeficient patient can be treated by IV ACV (5mg/kg body weight every 8 hours.

Varicella-zoster virus Cause varicella (chicken pox) Herpes zoster (shingles)

Varicella-zoster virus VZV is endemic in most populations primary infection is presumed to occur via the respiratory route at least 10% of the population remain uninfected

Varicells (chicken pox ) Acquired by respiratory rote Virus becomes latent in dorsal root ganglia May affect any sensory nerve (thoracic, trigeminal, cervical, lumbosacral) Viral DNA can be detected in sensory ganglia. Reaction cause the attack of herpes zoster (elderly and immuno- compromised)

Varicella (chicken pox ) Common childhood infection Incubation period of 2 weeks In children appear as rashes. Adult suffer more constitutional symptoms. Rashes are centripetal (more pronounced on the trunk than on limbs) Macule, papules, vesicles then form crusts that are shed from skin.

Complications Bacterial infection leads to formation of pustules In patients with thrombocytopenia rashes may become haemorrhagic. Post-infection encephalitis Pneumonia and generalised varicella in immuno- compromised patients. Leukaemic children are at particular risk of pneumonitis .

Herpes zoster Zoster derived from Latin words for a belt or girdle and refers to the characteristic distribution of the rash when thoracic dermatomes are involved. The attack is heralded by hyperaesthesia and some time pain in the affected area followed by appearance of typical herpetic vesicles that eventually crust over and heal.

Herpes zoster Complications Post-herpetic pain Ophthalmic zoster (ophthalmic branch of trigeminal nerve) is affected. Generalized zoster

Treatment Chicken pox Usually does not require antivirus ACV is useful for both prevention and treatment in immuno-compromised patient VZV can be treated by ACV (10mg/kg every 8 hours)

Beta herpesviruses human cytomegalovirus (HCMV) human herpesvirus 6 and 7

HCMV Human Cytomegalovirus Prevalence of HCMV in adult populations is 70% and is a result of: intrauterine infection perinatal infection intimate or sexual contact transfusion of whole blood, cellular products or solid organs

Latency HCMV appears to establish latent infection in cells of the monocyte/macrophage lineage HCMV must also persist in the cellular fraction of blood and in solid organs

Congenital Infection 10% of infected babies are born with disease, including jaundice, growth retardation hepato- splenomegaly and encephalitis At least 15% of neonates who are apparently asymptomatic develop intellectual impairment

Primary Infection

Primary infection primary infection with HCMV is almost always asymptomatic rarely primary infection leads to a ‘glandular fever’ syndrome: Sore throat. Fever. Lymphadenopathy (tender, enlarged lymph nodes). General malaise. Headache. Muscle aching. Erythematous rash involving the trunk.

Reactivation Disease pneumonitis, particularly following bone marrow transplantation. Mortality ~80% colitis adrenalitis retinitis, particularly in AIDS patients

HHV-6 recently discovered human herpesviruses infection with HHV-6 is ubiquitous and is the cause of ‘exanthem subitum, roseola infantum ’, a pyrexial illness of infancy (Fever and Rash). More than 95% of children older than one year and adults are virus positive Latency occur in gland, kidneys and lymphoid tissues.

HHV-6 Reactivation occur after hematopoietic stem cell transplantation (cases delay engrafment, CNS dysfunction, and increased mortality

HHV-7 Different from HHV-6. Share 50% homology on DNA level with HHV-6 Infection occurs in early childhood Persistent infections are established in salivary gland Primary infection with HHV-7 has been linked with roseola infantum

Gammaherpesviruses Epstein-Barr virus HHV-8

Epstein-Barr virus EBV has a seroprevalence of 80-90% EBV replicates in epithelial cells of the oro- pharynx EBV colonizes the memory B-cell where it establishes latent infection, which is characterized by the expression of a limited subset of virus genes, known as the “latent” genes 

Diseases Primary infection with EBV can cause the ‘glandular fever’ syndrome (infectious mononucleosis ) Chronic infection is associated with three important diseases: Burkitt’s lymphoma Hodgkin lymphoma and Non-Hodgkin Lymphoma, nasopharyngeal carcinoma other lymphomas

HHV-8 Also called Kaposi Sarcoma Associated Herpesvirus The genome is 165 kbp, contain numerous genes related to cellular regulatory genes involved in cell proliferation, apoptosis and host responses. The virus cause Kaposi Sarcomas (vascular tumors of mixed cellular composition. Transmitted through oral secretion, sexual contact, blood transfusion, organ transplant, and vertical transmission.