Herpesviruses An Overview

One of the largest human viruses ‘Herpein’ means to creep in ancient Greek There are nearly 100 viruses of the herpes group that infect many different animal species. Set up latent or persistent infection following primary infection Reactivation are more likely to take place during periods of immunosuppression Some members, such as the HSVs, undergo genome rearrangements, giving rise to different genome "isomers Virus morphology

Properties of herpesviruses Three subfamilies:  Alphaherpesvirinae- HSV-1, HSV-2, VZV (HHV-3) Short cycle, grow in epithelial, latent in neurons  Betaherpesvirinae- CMV (HHV-5), HHV-6, HHV-7 Long cycle, grow in lymphocyte, latent in gland and kidney (CMV), lymphoid (HHV 6,7)  Gammaherpesvirinae – EBV (HHV-4), HHV-8 Variable cycle, grow in B lymphocyte (trasformation), latent in lymphoid tissue

Herpes Simplex Viruses

HSV

Properties Belong to the alphaherpesvirus subfamily of herpesviruses The genome of HSV-1 and HSV-2 share % 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.

Epidemiology (1) HSV is spread by contact, as the virus is shed in saliva, genital and other secretions. 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 subclinical (without apparent sign) in most individuals. It is a disease mainly of very young children ie. those below 5 years.

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. Following primary infection, 45% of orally infected individuals and 60% of patients with genital herpes will experience recurrences.

Macule, papule, Vesicle, pustule and crust

Pathogenesis HSV spreads locally and a short-lived viremia occurs, whereby the virus is disseminated in the body. Spread with end of neurons to the ganglia or sacral. Spread 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; sunlight, and reduce immune system.

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

Herpetic infection (HSV-1)

Herpes gladiatorum Ocular herpes Herpetic whitlow Herpetic infection (HSV-1)

Genital Herpes (HSV-2) Genital lesions may be primary, recurrent. Latent in sacral neurons Genital herpes increases the risk of cervical cancer

Laboratory Diagnosis Direct Detection  Tzanck smear shows multinucleated gaint cells and crowdy type A inclusion (scrapping of the base of lasions)  Immunofluorescence of skin scrappings  PCR  Acyclovir, a nucleoside analouge

Cytopathic Effect of HSV in cell culture( syncytium,gaint multinuclear cell ) Positive immunofluorescence test for HSV antigen in epithelial cell. (Virology Laboratory, New-Yale Haven Hospital)

Varicella- Zoster Virus

Properties  Belong to the alphaherpesvirus subfamily of herpesviruses  One antigenic serotype only, although there is some cross reaction with HSV.

Epidemiology Primary varicella is an endemic disease. Varicella is one of the classic diseases of childhood, with the highest prevalence occurring in the years old age group. Varicella is highly communicable, with an attack rate of 90% in close contacts. Most people become infected before adulthood but 10% of young adults remain susceptible. Herpes zoster, in contrast, occurs sporadically and evenly throughout the year.

Pathogenesis Transmission with respiratory droplets After an incubation period of 14 days, the virus arrives at its main target organ, the skin. Following the primary infection, the virus remains latent in the cranials

Herpes Zoster (Shingles) It may occur at any age but the vast majority of patients are more than 50 years of age. The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment. There is a characteristic eruption of vesicles in the dermatome which is often accompanied by intensive pain which may last for months (postherpetic neuralgia)

Cytopathic Effect of VZV in cell culture: Note the ballooning of cells ( Eosinophilic inclusion in the nucleus). (Coutesy of Linda Stannard, University of Cape Town, S.A.) Cytopathic Effect of VZV Eosenophilic inclusion in nuclear  Acyclovir, a nucleoside analouge

Epstein-Barr Virus

Epstein-Barr Virus (EBV)  The major target cell for EBV is the B lymphocyte (CD21 or CR2)  The viral genome does not normally integrate into the cellular DNA but forms circular episomes which reside in the nucleus.  There are two major strains of EBV (types A and B).

Epidemiology % of children are seropositive. The virus is transmitted by contact with saliva, in particularly through kissing. Primary infections in children are usually subclinical In adolescents and young adults, the classic syndrome associated with primary infection is infectious mononucleosis (about 50% of infections).

Disease Association 1. Infectious Mononucleosis 2. Burkitt's lymphoma 3. Nasopharyngeal carcinoma 4. Hodgkin and non-Hodgkin lymphomas 5. Gastric carcinoma 6. Lymphoproliferative disease and lymphoma in the immunosuppressed patients.

Mononucleosis is a polyclonal stimulation of lymphocytes (Lymphocytosis). EBV-infected B cells synthesize immunoglobulin. Autoantibodies are typical of the disease, with heterophil antibody that reacts with antigens on sheep erythrocytes. S ymptoms of headache, fever, malaise, fatigue, and sore throat occur Enlarged lymph nodes and spleen are characteristic. Some patients develop signs of hepatitis Monospot test or paul-bunnell test (distinguish EBV from CMV, HHV6 and 7,,,) Infectious Mononucleosis

Burkitt’s Lymphoma (1) Burkitt lymphoma is a tumor of the jaw in African children and young adults A cancer of the lymphatic system (in particular, B lymphocytes) It usually occurs in children aged 3-14 years. It respond favorably to chemotherapy. Most African tumors (>90%) contain EBV DNA and express EBNA1 antigen. In other parts of the world, only about 20% of Burkitt lymphomas contain EBV DNA

Burkitt’s Lymphoma (2) It is speculated that EBV may be involved at an early stage in Burkitt lymphoma by immortalizing B cells. It is restricted to areas with holoendemic malaria. Therefore it appears that malaria infection is a cofactor.

Nasopharyngeal Carcinoma Nasopharyngeal carcinoma (NPC) is a malignant tumor of the squamous epithelium of the nasopharynx. It is very prevalent in S. China, where it is the commonest tumor in men and the second commonest in women. Multiple copies of EBV genome and EBV EBNA-1 antigen can be found in cells of undifferentiated NPC. Patients with NPC have high titres of antibodies against various EBV antigens. Besides EBV, it appears to be a number of environmental and genetic cofactors in NPC. In theory, NPC can be prevented by vaccination.

Immunocompromised Patients Immunodeficient patients are susceptible to EBV-induced lymphoproliferative diseases that may be fatal. From 1% to 10% of transplant patients develop an EBV-associated lymphoproliferative disorder, often when experiencing a primary infection. Aggressive monoclonal B cell lymphomas may develop. AIDS patients are susceptible to EBV-associated lymphomas and oral hairy leukoplakia, a wart-like growth that develops on the tongue; it is an epithelial focus of EBV replication.

Cytomegalovirus

Properties  More than 80% of people are seropositive  CMV is one of the most successful human pathogens, it can be transmitted vertically or horizontally usually with little effect on the host.

Pathogenesis Once infected, the virus remains in the person for life and my be reactivated from time to time, especially in immunocompromised individuals. The virus may be transmitted in utero, perinatally, or postnatally. Congenital infection (utero) - may result in cytomegalic inclusion disease (CID)

Cytomegalic Inclusion Disease CNS abnormalities - microcephaly, mental retardation, epilepsy, Eye - corhoidoretinitis and optic atrophy Ear - sensorineural deafness Liver - hepatosplenomegaly and jaundice which is due to hepatitis. Lung - pneumonitis Heart - myocarditis Haemolytic anaemia

Clinical Manifestations Perinatal infection - usually asymptomatic Postnatal infection - usually asymptomatic. However, in a minority of cases, the syndrome of infectious mononucleosis may develop which consists of fever, lymphadenopathy, and splenomegaly. The heterophil antibody test is negative although atypical lymphocytes may be found in the blood. Immunocompromised patients such as transplant recipients and AIDS patients are prone to severe CMV disease such as pneumonitis, retinitis, colitis, and encephalopathy. Reactivation or reinfection with CMV is usually asymptomatic except in immunocompromised patients.

Cytopathic Effect of CMV Basophilic inclusion in nuclear Enlarged cell with viral inclusion bodies (owl eyes)

Treatment & Control  Ganciclovir, a nucleoside analuge structurally related to acyclovir, has been used successfully in immunosuppressed patients.

Other Human Herpes Viruses

Properties of HHV-6 and 7 The main target cell is the T-lymphocyte, although B- lymphocytes may also be infected. It is thought that HHV-6 and HHV-7 are related to each other in a similar manner to HSV-1 and HSV-2 ( 50% homology at the DNA level).

Epidemiology and Pathogenesis They are transmitted mainly through contact with saliva and through breast feeding. HHV-6 and HHV-7 infection are acquired rapidly after the age of 4 months when the effect of maternal antibody wears off. By the time of adulthood, 90-99% of the population had been infected by both viruses.

Clinical Manifestations (1) Primary HHV-6 infection is associated with Roseala Infantum, which is a classical disease of childhood. Most cases occur in infants between the ages of 4 months and two years. A spiking fever develops over a period of 2 days followed by a mild maculopapular rash. The fever is high enough to cause febrile convulsions. There are reports that the disease may be complicated by encephalitis.

Clinical Manifestations (2) If primary infection is delayed until adulthood, there is a small chance that an infectious mononucleosis-like disease may develop in a similar manner to EBV and CMV. HHV-7 also have been linked with roseola infantum in infants and young children Although both viruses may be reactivated in immunocompromised patients.

Roseala Infantum

Human Herpes Virus 8 Originally isolated from cells of Kaposi’s sarcoma (KS) HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma KSHV is a lymphotropic and a vascular tumors of mixed cellular composition It is involved in the pathogenesis of body cavity-based lymphomas occurring in AIDS patients and of multicentric Castleman disease. The KSHV genome contains numerous genes related to cellular regulatory genes involved in cell proliferation, apoptosis, and host responses (cyclin D, cytokines, chemokine receptor) that presumably contribute to viral pathogenesis.

Kaposi’s Sarcoma