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HERPESVIREDAE Introduction • The word herpesvirus is derived from the Greek herpein, meaning to creep. • The order Herpesvirales currently consists of 3 families, 3 subfamilies, 17 genera, and > 90 species. • Herpesviruses found in mammals, birds, and reptiles constitute the family Herpesviridae. 2 Herpesviruses That Infect Humans Genus (HSV 1 or 2) (VZV) (CMV) (HHV) Genus (EBV) Genus 3 Introduction • A notable characteristic of herpesviruses is that, once they have infected a host, they commonly remain as persistent infections for the lifetime of the host. • These infections are often latent infections, which can be reactivated from time to time, especially if the host becomes immunocompromised. • Both primary and reactivated herpesvirus infections can either be asymptomatic or can result in disease of varying severity. 4 Major Characteristics • Herpesviruses are DNA viruses. • DNA is linear and double stranded. • Their diameter ranges from 120 to 200 nm. • They are enveloped. • Their capsid is icosahedral composed of 162 capsomeres. An electron micrograph of HSV 5 6 Replication 1. 2. 3. 4. 5. 6. 7. 8. 9. Attachment to the host cell Fusion of viral envelope with the cell membrane Uncoating DNA migrates to host cell nucleus Transcription, mRNA migrates to the cytoplasm for translation, proteins migrate to the nucleus Replication to yield many genomes Assembly takes place in nucleus Virus envelope is derived from the nuclear membrane Transport to the outer cell membrane and release 8 9 7 6 5 4 3 1&2 7 8 9 7 6 5 4 3 1&2 8 Herpes Simplex Virus (HSV) • There are two distinct herpes simplex viruses: • Type 1 and type 2 (HSV-1, HSV-2) • They differ in their mode of transmission. • HSV type 1 (Human herpes virus type 1 or HHV type 1) is usually isolated from lesions in and around the mouth and is transmitted by direct contact or droplet spread from cases or carriers. • HSV type 2 (HHV type 2) is transmitted sexually or from a maternal genital infection to a newborn. 9 Herpes Simplex Virus (HSV) • Epidemiology • Herpes simplex types 1 and 2 are found worldwide, only in humans. • Herpes simplex type 2 has traditionally been associated with genital herpes, and type 1 with oral herpes, but type 1 is believed to cause 20–25% of genital herpes cases. • Seroprevalence of HSV-1 worldwide is about 90%, although in developed countries it is below 70%. • HSV-2 has a seroprevalence of about 25% in some developed countries. • It is believed that HSV-2 seroprevalence is lower than for HSV-1 because of partial protection supplied by an initial HSV-1 infection 10 Herpes Simplex Virus (HSV) • Transmission • • • • • Saliva, Vaginal secretions, Secretions from blisters in oral and anogenital tracts Eyes; skin lesions Herpes simplex virus type 1: • mainly oral; • Herpes simplex virus type 2: • mainly sexual 11 Herpes Simplex Virus (HSV) • Pathogenesis • The mechanisms involved in the pathogenesis of HSV-1 and HSV-2 are very similar. • Both viruses initially infect and replicate in mucoepithelial cells and then establish latent infection in neurons. • Skin and mucous membranes are the portals of entry in which the virus also multiplies, causing lysis of cells and formation of blisters . • Soon after replication is under way in the skin or a mucous membrane, virions travel to the root ganglia via the sensory nerves supplying the area. • The virus then becomes latent in the ganglia. 12 13 Herpes Simplex Virus (HSV) • Clinical Features • Gingivostomatitis; vesicles on the gums and oral mucosa, break down to form ulcer • Eczema herpeticum • Keratoconjunctivitis • Meningitis and encephalitis 14 Herpes Simplex Virus (HSV) • Laboratory Diagnosis • Cell culture in human diploid cells: CPE may include foci of enlarged cells, some of which are multinucleated. • Stained smears of an active lesion often reveal multinucleated cells containing intranuclear inclusions. • Detection of antibodies (ELISA) • Polymerase chain reaction is useful for detecting viral DNA in cerebrospinal fluid when herpetic infection of the CNS is suspected 15 Herpes Simplex Virus (HSV) • Control and Treatment • Vaccination (split vaccine), an experimental one. • Acyclovir is the drug of choice. • It inhibits viral DNA polymerase • Idoxuridine, a nucleoside analogue • for ophthalmic infection, topical 16 Varicella-Zoster Virus (VZV) • Subfamily: Alphaherpesviruses • Genus: Varicellovirus • Species: Varicella-zoster virus • Causes chickenpox (varicella) and, with recurrence, causes herpes zoster or shingles. • Varicella (chickenpox) and herpes zoster are different manifestations of the same virus infection. 17 Varicella-Zoster Virus (VZV) • Characteristics of the Virus • Varicella-zoster virus is morphologically identical to herpes simplex virus. • It can be grown in cultures of human fibroblasts or HeLa cells. • Cytopathic changes are more focal and spread much more slowly than those induced by HSV 18 Varicella-Zoster Virus (VZV) • Transmission • Aerosol • At risk • Immunosuppression • Distribution • Worldwide • No seasonal incidence • Vaccines or antiviral drugs • Attenuated vaccine • Antiviral drugs: acyclovir, foscarnet • DNA polymerase inhibitors 19 Varicella-Zoster Virus (VZV) • Varicella (chickenpox) • Varicella (chickenpox) is one of the mildest highly communicable and most common of childhood infections. • It is usually a mild disease of childhood and is normally symptomatic, although asymptomatic infection may occur. • The portal of entry of the virus is the respiratory tract or conjunctiva. • After an incubation period of about two weeks (7–23 days) the lesions begin to appear 20 Varicella-Zoster Virus (VZV) Varicella (chickenpox) • In children, there is little prodromal illness and the disease is first noticed when skin lesions appear. • The rash is mainly affecting the trunk, and is very superficial without involving the deeper layers of the skin. • The rash appears in successive crops, so that all stages of the eruption can be seen at the same time. • It matures very quickly, beginning to crust within 48 hours. • Recovery is usually uneventful. 21 Varicella-Zoster Virus (VZV) Varicella (chickenpox) • Complications • Primary infection is usually more severe in adults than in children. • The rash may become hemorrhagic. • Varicella pneumonia is more common in adults. • A variety of organs may be affected with complications like myocarditis, nephritis, meningitis and encephalitis. • Secondary bacterial infections. • Reyes’ syndrome may follow varicella in some cases with a history of administration of salicylates. 22 Varicella-Zoster Virus (VZV) Herpes Zoster (Shingles, zona) • While varicella is typically a disease of childhood, herpes zoster is one of old age. • Herpes zoster usually occurs in persons who had chickenpox several year earlier. • The virus remaining latent in the sensory ganglia, may leak out at times but is usually held in check by the residual immunity. • It is believed that years after the initial infection, when the immunity has decreased, the virus may be reactivated, travel along the sensory nerve to produce zoster lesions on the area of the skin or mucosa supplied by it. 23 HERPES ZOSTER (SHINGLES, ZONA) • Complications • Postherpetic pain: In the affected area is frequent, particularly in the elderly. • Ophthalmic zoster • Generalized zoster 24 HERPES ZOSTER (SHINGLES, ZONA) • laboratory diagnosis • Diagnosis is usually clinical. • Microscopy: Multinucleated giant cells • Direct examination by electron microscopy will reveal herpes particles. • Virus isolation • Virus antigen: The virus antigen can be detected in scrapings from skin lesions by immunofluorescence • ELISA and PCR techniques are also in use. • Serological diagnosis: A rise in specific antibody titer can be detected in the patient’s serum by various tests, including latex agglutination, and ELISA. 25 HERPES ZOSTER (SHINGLES, ZONA) • Prophylaxis and treatment • Active Immunization • Attenuated vaccine • Passive Immunization • Varicella-zoster immunoglobulin (VZIG) seems to be of some use in preventing or modifying severe disease in immunodeficient patients. 26 CYTOMEGALOVIRUS (CMV), HHV 5 • Cytomegaloviruses (CMV), formerly known as salivary gland viruses, are a group of ubiquitous herpesviruses of humans and animals. • Cytomegalovirus (CMV) means ‘large cell virus’ and it refers to the swollen cells which contain large intranuclear inclusions that characterize this viral infection. • Following primary infection, the virus can remain in a latent form in secretory glands, lymphoreticular tissue, kidney and other tissue and may reactivate at any time. 27 CYTOMEGALOVIRUS (CMV), HHV 5 • Epidemiology • Transmission • Blood, tissue and body secretions (urine, saliva, semen, cervical secretions, breast milk, tears) • At risk or risk factors • • • • Babies whose mothers become infected during pregnancy Sexual activity Transplant recipients Immunosuppression • Distribution • Worldwide • No seasonal incidence 28 CYTOMEGALOVIRUS (CMV) • Pathogenesis • Infects epithelial and other cells • Mainly causes subclinical infections • Latent infection in CD34+ bone marrow progenitor cells (differentiate into all the various blood cell types). • Immunosuppression leads to recurrence and severe disease 29 CYTOMEGALOVIRUS (CMV) • Laboratory diagnosis • Specimens: CMV can be isolated from the urine, saliva, breast milk, semen, cervical secretions and blood leucocytes. • Demonstration of cytomegalic cell: The histologic hallmark of CMV infection is the cytomegalic cell, which is an enlarged cell that contains a dense, central, “owl’s-eye,” • Isolation of virus • DNA probes: DNA probes are used to directly detect the CMV antigens in tissues or fluids. • Polymerase chain reaction (PCR): To directly detect the genome in tissues or fluids. • Serology: IgM antibodies suggests a current infection and can be detected in serum by ELISA. 30 CYTOMEGALOVIRUS (CMV) 31 CYTOMEGALOVIRUS (CMV) • Treatment and Prevention • Ganciclovir and foscarnet have been approved for the treatment of CMV infections. • Screening of blood and organ donors and administration of CMV immunoglobulins have been employed in prevention. • No vaccine is available 32 Epstein-Barr Virus (EBV),HHV 4 • Epstein–Barr virus (EBV) is in some respects the most sinister herpesvirus, for its association with malignant disease is now well established. • Mainly human B cells have receptors for the virus. • EBV infected B cells are transformed so that they become capable of continuous growth in vitro. 33 Epstein-Barr Virus (EBV) • Epidemiology • Epstein-Barr virus (EBV) infection is common amongst people living in developing countries. • Children are subclinically infected early in life. • In developed countries, infection generally occurs in early adulthood and infected individuals may present with infectious mononucleosis. • Infection is mostly acquired by the oral route “kissing disease”. • Evidence of sexual transmission and transmission during blood transfusion and organ transplantation have been noted. • Transmission • Saliva, close oral contact, or shared items (cup or toothbrush) • Vaccines • No vaccine against EBV is currently available. 34 Epstein-Barr Virus (EBV) • Pathogenesis • EBV infects and results in lysis of oropharyngeal epithelial cells, from where it may spread to passing B-cells in the associated lymphoid tissue. • B-lymphocytes are infected and immortalised by the virus, resulting in a state of polyclonal activation. • Most of the B-cells remain latently infected for life, while a small percentage may undergo a lytic infectious cycle. • The infection is controlled by an intact cellular immune response where cytotoxic T-cells play a pivotal role. • Memory B-cells are the main reservoirs for EBV reactivation and for the development of virus-related malignancies. 35 36 Epstein-Barr Virus (EBV) • Clinical conditions 1. Infectious mononucleosis 2. EBV associated malignancies: a) Burkitt’s lymphoma b) Nasopharyngeal carcinoma 37 Epstein-Barr Virus (EBV) 1. Infectious Mononucleosis (Glandular Fever) • This is an acute self-limited illness usually seen in nonimmune young adults. • The incubation period is 4–8 weeks. • Infectious mononucleosis is characterized by high fever, malaise, pharyngitis, lymphadenopathy (swollen glands), and, often, hepatosplenomegaly. • A mild transient rash may be present. • Some patients treated with ampicillin may develop a maculopapular rash due to immune complex reaction to the drug. • The typical illness is self-limited and lasts 2–4 weeks. 38 Epstein-Barr Virus (EBV) • Laboratory Diagnosis • Hematological findings & Serological tests: • Leukocyte count (20x109/liter, 50% are lymphocytes, 20% are atypical) • T-cells react against viral antigens on B-cells and kill them • Heterophile antibodies: • B-cells transformed by EBV undergo polyclonal expansion, they produce antibodies with a number of specificities, • e.g., one is directed against ampicillin, • others agglutinate sheep or horse RBC • Specific antibodies: • Antibody to EA (early antigen) indicates current or recent infection as does IgM antibody to VCA (viral capsid antigen) whereas, IgG antibody to VCA is evidence of past infection. 39 40 Epstein-Barr Virus (EBV) 1. Infectious Mononucleosis (Glandular Fever) • Complications • They are rare but some are serious: • Acute airway obstruction • Splenic rupture • Neurological complications include meningitis and encephalitis 41 Epstein-Barr Virus (EBV) EBV associated malignancies: a) Burkitt’s lymphoma • Epstein–barr virus (EBV) is associated with the development of Burkitt’s lymphoma (a tumor of the jaw in African children and young adults). • Most African tumors (>90%) contain EBV DNA and express EBNA1 antigen. • Malaria, a recognized cofactor. 42 Epstein-Barr Virus (EBV) EBV associated malignancies: b) Nasopharyngeal Carcinoma • This cancer of epithelial cells is common in males of Chinese origin. • It mainly affects people aged 20–50 years, majority are males. • EBV DNA is regularly found in nasopharyngeal carcinoma (NPC) cells. • Genetic and environmental factors are believed to be important in the development of nasopharyngeal carcinoma 43