Herpes

• EBV Structure


  linear, DNA virus, enveloped
• Herpes viruses


  Enveloped DNA virus, Icosahedral core surrounded by a lipoprotein envelope, Linear double-stranded DNA, Large (120–200 nm in diameter), Capsid surrounds DNA core and over the capsid is tegument (a protein-filled region), Viral-Specific Enzymes (DNA polymerase & Thymidinekinase)
• Nine human herpesvirus species


  • Herpes Simplex Virus type 1 (HSV-1)
  • Herpes Simplex Virus type 2 (HSV-2)
  • Varicella-Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Epstein-Barr Virus (EBV)
  • Human Herpes Virus type 6 (HHV-6)
  • Human Herpes Virus type 7 (HHV-7)
  • Human Herpes Virus type 8 (HHV-8)
  • Herpes B Virus/CercoPethicine Herpesvirus-1 (CHV-1)
• Classification of herpesviruses


  • Alphaherpesvirinae (herpes simplex virus group)
  • Betaherpesvirinae (cytomegalovirus group)
  • Gammaherpesvirinae (lymphoproliferative group)
• All Herpesviruses


  • Icosahedral
  • Enveloped
  • Double stranded DNA genome
  • DNA homology: HSV 1 & 2 (50%), HHV 6 & 7 (30-50%)
  • Viral-Specific Enzymes: DNA polymerase & Thymidinekinase
• Characteristic Disease of All Herpesviruses


  • Primary Infection
  • Latent Infection
  • Reactivation (frequently, but not always, associated with Further disease)
• Some HHVs are associated with tumors and/or carcinoma
• Associations of HHVs with tumors/carcinoma


  • HSV-2 associated with Cervical Carcinoma
  • CMV associated with Colonic Carcinoma, Prostatic Carcinoma, Cervical Carcinoma
  • EBV associated with Nasopharyngeal Carcinoma, Burkitt's lymphoma
  • HHV-8 associated with Kaposi sarcoma in HIV
• Herpes Simplex Viruses


  Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are distinguished by Antigenicity and location of lesions
• EBV target cell


  B lymphocyte
• Characteristics of HSV-1


  • Above the waist, primarily in adults
  • Acute gingivostomatitis
  • Recurrent herpes labialis (cold sores)
  • Keratoconjunctivitis (keratitis)
  • Encephalitis
• EBV infection of B cells


  1. Binding to viral receptor (CR2 or CD21)

  2. Enters latent state without complete viral replication
• Diseases associated with EBV


  • Acute infectious mononucleosis
  • Nasopharyngeal carcinoma
  • Burkitt lymphoma
  • Hodgkin and non-Hodgkin lymphomas
  • Lymphoproliferative disorders in immunodeficient individuals
  • Oral hairy leukoplakia in AIDS patients
  • Gastric carcinoma
  • Interstitial Pneumonitis

  
• Characteristics of HSV-2


  • Below the waist
  • Herpes genitalis (genital herpes)
  • Neonatal encephalitis and other forms of neonatal herpes
  • Aseptic meningitis
• EBV antigen classes


  • Latent phase antigens (EBNAs and LMPs)
  • Early antigens (nonstructural proteins)
  • Late antigens (structural components of viral capsid and envelope)
• Humans are the natural hosts of both HSV-1 and HSV-2
• Viral capsid antigen (VCA) is detected in virus producing cell lines
• EBV transmission and epidemiology


  • Commonly in saliva (active and latent virus infections)
  • Very rare by blood, vice versa (CMV infection)
  • 12-18 months after recovery, virus excreted from oropharynx in saliva (kissing disease)
  • EBV infection is one of the most common infections worldwide (90% in USA, 70-80% in western countries)
  • Adults are latently infected, evidenced by presence of EBV antibodies
• Replication cycle of herpes simplex virus


  1. Attachment (Cellular Receptors = Heparan Sulphate)

  2. Fusion (Virus fuses with plasma membrane)

  3. Uncoating (Viral DNA is released from capsid at nuclear pore, circularization of genome)

  4. Transcription of Alpha genes (transcription of immediate-early genes), translated to Alpha-proteins (Cellular Preparation)

  5. New transcription round Beta-proteins, products of early genes, function in DNA replication

  6. Viral DNA replication

  7. New transcription round-Gamma-proteins (products of late genes and consisting primarily of viral structural proteins, Structural Proteins = Empty Capsids)

  8. Viral DNA is packaged into preformed empty nucleocapsids in the cell nucleus

  9. Accumulation of viral glycoproteins in the nuclear membrane

  10. Get Envelope from nuclear membrane

  11. Viruses go out the cell through (Endoplasmic Reticulum)
• Primary EBV infection


  1. Virus replication in epithelial cells or surface B lymphocytes of pharynx and salivary glands

  2. Infected B cells spread infection throughout body

  3. In normal individuals, most virus-infected cells eliminated but small numbers of latently infected lymphocytes persist
• The length of the replication cycle varies from about 18 hours for HSV to more than 70 hours for CMV
• HSV - Replication


  Diagram showing the steps in the replication cycle of herpes simplex virus
• Pathology of HSV


  • Cytolytic infections, pathologic changes due to necrosis of infected cells and inflammatory response
  • Lesions induced in the skin and mucous membranes by HSV-1 and HSV-2 are the same, changes induced by HSV are similar for primary and recurrent infections but vary in degree
  • Characteristic histopathologic changes include ballooning of infected cells, production of Cowdry type A intranuclear inclusion bodies, margination of chromatin, and formation of multinucleated giant cells
  • Cell fusion (cell-to-cell spread of HSV)
• Primary Infection


  HSV is transmitted by contact of a susceptible person with an individual excreting virus, virus must encounter mucosal surfaces or broken skin, viral replication occurs first at the site of infection, virus then invades local nerve endings and is transported by retrograde axonal flow to dorsal root ganglia where latency is established, primary HSV infections are usually mild, HSV can enter the central nervous system and cause meningitis or encephalitis, widespread organ involvement can result in an immunocompromised host
• Primary EBV infections in children are usually subclinical, but if they occur in young adults, acute infectious mononucleosis often develops

  
• EBV-infected B cells synthesize immunoglobulin, with autoantibodies typical of the disease, including heterophil antibody that reacts with antigens on sheep erythrocytes
• Latent Infection


  Virus resides in latently infected ganglia in a non replicating state, viral persistence in latently infected ganglia lasts for the lifetime of the host, provocative stimuli can reactivate virus from the latent state, the virus transits via axons back to the peripheral site, and replicate at the skin or mucous membranes, humoral and cellular immunity limits local viral replication so that recurrent infections are less extensive and less severe, many recurrences are asymptomatic
• Herpes simplex risk factors for reactivation


  • Oral/Genital lesions
  • Sun light
  • Fever
  • Menstruation
  • Stress
  • Trauma
  • HIV
  • Chemotherapy
  • Transplant (70%)
  • Skin disease
  • Burns
  • Steroids
  • Pregnancy
• Transmission

  HSV 1 transmitted primarily in saliva, HSV 2 transmitted by sexual contact, Oral–genital sexual activity: HSV-1 infections of the genitals and HSV-2 lesions in the oral cavity (10–20% of cases), HSV-2 infections has markedly increase comparatively
• Clinical Findings - Oropharyngeal Disease


  • Most frequently in small children (1–5 years of age)
  • Involves the buccal and gingival mucosa of the mouth
  • Incubation period is short (about 3–5 days, with a range of 2–12 days)
  • Clinical illness lasts 2–3 weeks
  • Symptoms include fever, sore throat, vesicular and ulcerative lesions, gingivostomatitis, and malaise
  • Gingivitis (swollen, tender gums) is the most striking and common lesion
  • Primary infections in adults commonly cause pharyngitis and tonsillitis, localized lymphadenopathy may occur
  • Recurrent disease is characterized by a cluster of vesicles most commonly localized at the border of the lip, intense pain occurs at the onset but fades over 4–5 days, lesions progress through the pustular and crusting stages, and healing without scarring is usually complete in 8–10 days