L18 - Gammaherpesvirus

• Gammaherpesviruses have a very restricted host range
• In vitro all members infect lymphobastoid cells and some cause infection in epithelial or fibroblastic cells

  
• Gammaherpesviruses typically target B or T lymphocytes

  
• Genera of Gammaherpesviruses


  • Lymphocryptovirus
  • Rhadinovirus
  • Percavirus
  • Macavirus

  
• Lymphocryptovirus


  Mainly infect humans and non-human primates and includes human gammaherpesvirus 4 = Epstein Barr Virus

  
• Rhadinovirus


  Mainly infect human and non-human primates and includes human gammaherpesvirus 8 = Kaposi's Sarcoma Virus

  
• Gammaherpesviruses have a dsDNA genome

  
• EBV genome


  ~ 170 kbp, ~ 100 protein coding genes, also non-coding RNAs and miRNAs (>46)

  
• KSHV genome


  ~ 165 kbp, at least 80 protein coding genes, also non-coding RNAs and miRNAs

  
• In both cases linear dsDNA in particles but found as a closed circular dsDNA in the nucleus of persistently infected cells "episome"

  
• Epstein Barr Virus causes the most common persistent asymptomatic virus infection in humans

  
• EBV infects 90-95% of the human population as a life long persistent infection
• EBV was the first human tumour virus to be discovered (1964)

  
• Diseases associated with EBV

  • Infectious mononucleosis
  • Human cancers (200,000 / year ; 1.8% of all cancer deaths)
  • Multiple sclerosis

  
• EBV is primarily found in the body as a latent infection of B cells

  
• EBV's dsDNA genome was completely sequenced in 1983

  
• Transmission of EBV


  By saliva
• Globally, most people are infected by EBV by the age of 5-8
• In resource-rich environments EBV infection is frequently delayed until adolescence or early adulthood
• Prevalence of infectious mononucleosis is dependent on age of initial EBV infection in different countries

  
• In many cases EBV associated cancers are most prevalent in specific geographical areas
• Infectious mononucleosis (IM)


  Also known as "kissing disease" or glandular fever
• Chronic IM


  Chronic disease/immune dysfunction
• Fatal IM


  1. linked genetic T-cell defect
• Fatal lymphoproliferative (B-cell) disorders can occur in various immunosuppressive conditions: after organ transplant / AIDS
• Burkitt's lymphoma (BL)


  Aggressive non-Hodgkin B-cell lymphoma associated with EBV, HIV and chromosomal translocations resulting in c-myc oncogene overexpression

  
• Nasopharyngeal carcinoma (NPC)


  Epithelial cell tumour associated with EBV latency, EBV almost always present in malignant epithelial cells

  
• Hodgkin's and non-Hodgkin's lymphomas are 50% EBV positive

  
• EBV is associated with gastric carcinomas
• EBV is associated with natural killer (NK) / T cell lymphomas

  
• There is a direct association between EBV infection and multiple sclerosis

  
• The EBV attachment protein gp350/220 and four core fusion glycoproteins—gB, gp42, and the gH/gL complex—are important for EBV entry into both epithelial cells and B-cells and targets for neutralizing antibodies

  
• As age increases to young adult, primary EBV infection more often causes infectious mononucleosis, which is linked to host genetics

  
• Up to 50% of resting memory B cells may be infected in the acute phase of infectious mononucleosis
• Infectious mononucleosis is characterised by a rapid expansion in NK cells and CD8+ T cells, a strong inflammatory response, and the emergence of atypical lymphocytes

  
• In latently infected cells, the EBV genome is maintained as a transcriptionally silent genome

  
• The EBV genome is circularised and if the cell divides then the virus genome is replicated and each daughter cell gets a copy of the virus

  
• This is achieved by the EBV protein EBNA1 which binds to the virus genome and interacts with dividing chromatin

  
• EBNA1 is the only EBV protein expressed in all types of latency

  
• Some EBV latent gene products promote cell growth while others inhibit it