Human herpesviruses Three subfamilies (genome structure, tissue tropism, cytopathologic effect, site of latent infection) Alphaherpesvirinae: Human herpesvirus 1 Herpes simplex type 1 HSV-1 Human herpesvirus 2 Herpes simplex type 2 HSV-2 Human herpesvirus 3 Varicella-zoster virus VZV Gammaherpesvirinae Human herpesvirus 4 Epstein-Barr virus EBV Oncogenic Human herpesvirus 8 Kaposi’s sarcoma related virus HHV-8 Oncogenic Betaherpesvirinae Human herpesvirus 5 Cytomegalovirus CMV Congenital inf Human herpesvirus 6Herpes lymphotropic virus HHV-6 Human herpesvirus 7 Human herpesvirus 7 HHV-7

Human herpesviruses Large, enveloped double stranded DNA viruses Icosahedral capsid Sensitive to acid, solvents, detergents and drying

Human herpesviruses They have common: Virion morphology Basic mode of replication Capacity to establish latent and recurrent infections, in case of EBV immortalizing infections Ubiquitous Usually cause benign disease especially in children In immunosuppressed people they cause significant morbidity and mortality

Human herpesviruses -DNA polymerase: -viral DNA replication -good target for antiviral drugs. -DNA replication and assembly:nucleus -buds from nuclear membrane, released by exocytosis and cell lysis. -lytic,persistant, latent, for EBV immortalizing infections

Herpes simplex virus Two types: HSV-1 and HSV-2 HSV can infect most types of human cells and even cells of other species. Lytic infection of fibroblasts and epitelial cells but latent infection of neurons The primary target cell: mucoepitelial cells Site of latency: neurons

Herpes simplex virus Means of spread: HSV-1 close contact, HSV-2 close contact+sexual transmission! Generally cause infection at the site of infection HSV-1: infections above the waist HSV-2: infections below the waist Growth characteristics are different HSV-2 :more potential for viremia

Herpes simplex virus Disease initiates by direct contact, depends on the infected tissue (oral, brain, genital) Direct cytopathologic effect Lytic infections of most cells, latent infection of neurons(hides from immune response) Cell to cell spread-syncytia(avoids antibody) Cowdry type A acidophilic intranuclear inclusion bodies

Herpes simplex virus Initiates infection through mucosal membranes or breaks in the skin Virus replicates in the cells at the base of the lession and infects the innervating neurons Travels by retrograde transport to the ganglion( trigeminal ganglion for oral HSV, sacral ganglia for genital HSV)

Herpes simplex virus Then turns to initial site of infection May be inapparent or vesicular( vesicle fluid contains infectious virons) Tissue damage: viral pathology+immunopathology Heals without a scar Latent infection occurs in neurons

Herpes simplex virus Recurrence: stress, trauma, fever, sunlight) The virus travels back down the nerve causing lessions at the dermatome Recurrences are less severe and more localized

HSV-1 is common 90% have antibody by 2 years of age HSV-2 occurs later in life with sexual activity Physicians,nurses,dentists at risk for infection of fingers (herpetic whitlow) Immunocompromised people and neonates at risk of disseminated, life-threateneing disease.

Laboratory diagnosis Cytology and histology: Tzanck smear(scraping of the base of a lesion), Papanicolaou smear or biopsy specimen Cytopathic effects: syncytia, ballooning of cytoplasm, Cowdry A intranuclear inclusions Direct antigen detection: immunofluorescence method or immunoperoxidase method DNA :in situ hybridization or PCR in tissue or vesicle fluid

Laboratory diagnosis Virus isolation: not routine now Serology:primary infection, type specific antibody by ELISA (differentiates HSV-1 and HSV-2)

Varicella-Zoster Chickenpox(varicella) With recurrence :herpes zoster-shingles:zona Primary target cell: mucoepitelial cell Site of latency: neuron Means of spread: respiratory and close contact Viremia occurs after local replication :skin lessions over the entire body

Varicella-Zoster Primary VZV infection: mucosa of respiratory tract Viremia Reticuloendotelial system,liver,spleen 11-13 days later secondary viremia Virus is spread through the body and skin=rash+fever+systemic symptoms

Varicella-Zoster Latent in dorsal root or cranial nerve ganglia after primary infection Reactivates in older adults and in patients with impaired immunity. On reactivation : a vezicular rash along the entire dermatome Children and leukemia: VZV more serious and more disseminated disease

Varicella-Zoster Extremely communicable Rates of infection exceeds 90% among household contact Contagious before and during symptoms. HZ develops in 10-20% of people infected with VZV and contains viable virus.

Varicella-Zoster Laboratory diagnosis: Cytology Virus isolation: difficult NAT Serology Treatment: ACV,famciclovir and valacyclovir Prophylaxis: VZIG:varicella-zoster immunoglobulin:immunosuppressed patients A live attenuated vaccine(Oka strain)

Epstein-Barr Virus Heterophile antibody-positive infectious mononucleosis Chronic disease Associated with endemic Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma, B-cell lymphomas in patients with acquired or congenital immunodeficiencies. Hairy oral leukoplakia Mitogen for B cells and immortalizes them

Epstein-Barr Virus Gammaherpesvirinae: Primary target cell: B cells and epitelial cells Site of latency: B cell Means of spread: saliva (kissing disease) Limited host range and tissue tropism: receptor for C3d component of the complement system (CR2 or CD21) which is expressed on B cells of humans and some epitelial cells of oro- and nasopharynx.

EBV-associated neoplasms Geographic distribution Co-factor? Endemic Burkett’s lymphoma: Africa:malaria Nasopharyngeal carcinoma: China

Laboratory diagnosis Heterophile antibody: results from nonspecific activation of B cells by EBV IgM antibody recognizes Paul-Bunnell antigen on sheep, horse and bovine erythrocytes not on guinea pig kidney cells Detected at the end of first week , lasts for several months Monotest, ELISA: specific antibodies VCA-IgM, antibody to early antigen (EA): recent infection VCA-IgG, EBNA: previous infection PCR

Cytomegalovirus(CMV) Betaherpesvirnae: lymphotropic Primary target cell: monocyte, lymphocte, epitelial cell Site of latency: monocyte, lymphocyte and? Means of spread: close contact, transfusions, tissue transplant and congenital

Clinical findings Predominant presentation: asymptomatic Neonates: deafness, mental retardation Immunosuppressed patients: disseminated dissease, severe disease (pneumonia, retinitis, colitis, esophagitis)

Congenital infection An important cause of congenital disease Serious birth defects is high if primary infection occurs during pregnancy Microcephaly, intracerebral calcification,hepatosplenomegaly,rash(cytomegalic inclusion disease), unilateral or bilateral hearing loss, mental retardation CMV in the urine in the first week (culture,PCR)

Laboratory tests Cytology and histology: ‘OWL’s eye’ inclusion body basophilic intranuclear:Urine not so sensitive Antigen in peripheral leucocytes DNA by PCR Cell culture: Human diploid fibroblasts Serology: primary infection(IgM by ELISA)

Human herpesvirus 6 Betaherpesvirinae Lymphotropic , ubiquitous Primary target cell: T cells and ? Site of latency: T cells and ? Means of spread: Respiratory, close contact Exanthema subitum: roseola A mononucleosis syndrome and lympadenopathy

Human herpesvirus 8 HHV-8 DNA sequences were discovered by PCR in biopsy specimens of Kaposi’s sarcoma (characteristic opportunistic diseases associated with AIDS) Primary effusion lymphoma (rare type of B-cell lymphoma) Multicentric Castleman’s disease

Human herpesvirus 8 Kaposi’s sarcoma-related virus Primary target cell: Lymphocyte and other cells Site of latency:? Means of spread: close contact, sexual, saliva? Limited to certain geographic areas (Italy, Greece, Africa) and AIDS

Human herpesvirus 8 Laboratory diagnosis: Serology: specific antibodies:IFA IgG,IgM HHV-8 DNA by PCR

Antivirals Herpes Simplex 1 and 2 Acyclovir Penciclovir Valacyclovir Famciclovir Adenosine arabinoside (ara-A) Trifluridine

Antivirals Varicella-Zoster Virus Acyclovir Famciclovir Valacyclovir Varicella-zoster immune globulin (VZIG) Zoster immune plasma Live vaccine Epstein-Barr Virus None

Antivirals Cytomegalovirus Ganciclovir* Valganciclovir* Iododeoxyuridine Foscarnet* Trifluridine Cidofovir*

Herpesvirus simiae(B virus) Asian monkeys Bites, saliva Encephalopathy in humans fatal