Gammaherpesvirus Flashcards
What are gammaherpesviruses?
- herpesvirus
- dsDNA genome
- infect lymphoblastoid cells and some epithelial cells
- typically target and latently infect T and B cells
- Epstein Barr Virus, Kaposi’s Sarcoma Virus
Describe EBV
- most common persistent asymptomatic infection in humans
- 90-95% of the population
- first human tumour virus to be discovered
- latently infects B cells
Name 3 diseases EBV is associated with
- human cancers
- infectious mononucleosis
- multiple sclerosis
How is EBV transmitted?
What age group is most commonly affected?
What affects associated diseases?
- transmitted through saliva
- most people are infected by the age of 8 but can be older in resource-rich places
- EBV-associated cancers are more and less prevalent in different geographical areas
What are some diseases associated with EBV infection?
- infectious mononucleosis - chronic immune dysfunction
- B cell disorders and cancers
- multiple sclerosis
What are some cancers associated with EBV infection?
- Burkitt’s lymphoma
- nasopharyngeal carcinoma
- Hodgkins and non-Hogkins lymphomas
- 50% of people with these cancers have encountered EBV
Describe the EBV virion structure
- envelope glycproteins allow entry and antigenicty
- nucleocapsid surrounds the DNA
- tegument proteins like all herpesviruses
Describe the EBV genome
- linear but forms a circle in the host nucleus
- many miRNAs are important in its latency
- EBNA regions of RNA are involved in perturbing host innate responses
- EBER 1-6 and LMP proteins involved in latency
How does EBV enter cells?
- attachment protein, 4 fusion proteins and gH/gL complex important here
- targets for neutralising Abs and vaccines
- interacts with CD21 on epithelial and B cells
- additionally interacts with CD35 and MHC II on B cells
How does EBV infect and go from primary to latent infection?
- enters epithelial cells in the oro-pharynx and may replicate here
- transcytoses through these to CD21 B cells
- lymphoid organs such as tonsils establish pools of latently infected B cells
- can sometimes reactivate and infect oro-pharyngeal epithelial cells and shed virus into the saliva
- unsure of causes
What are the risk factors of infectious mononucleosis?
- host genetics
- increased age at initial EBV infection
What is infectious mononucleosis infection like?
- high EBV replication in B cells in the oral cavity with up to 50% of memory B cells infected during the acute phase
- rapid expansion of NK cells and CD8+ T cells
- strong inflammatory response
- fever, swollen glands for weeks
- extreme tiredness for months
Describe the genome in latent EBV
- transcriptionally silent and circularised
- if the cell divides the genome is replicated with it
- virus protein EBNA1 binds the genome and interacts with dividing chromatin to ensure this
- 9 EBNA proteins are produced during latency but EBNA1 is the only one produced in all stages and is required for latent genome replicatin
What kinds of roles do EBV latent proteins play?
- reduce apoptosis
- regulate tumourgenesis pathways
- many are required for the transformation of different B cells into latency-infected cells
- others are involved in evading the immune response and aren’t vital for transformation
What are the functions of EBV latent non-coding RNAs / miRNAs?
- maintain latency by targeting EBV lytic genes and modulating LMP1 expression
- BART miRNAs target proapoptotic proteins and can inactivate TSGs
- BHRF1 miRNAs aid in B cell transformation to latency
- EBER1+2 contribute to the activation of innate immunity
What are the stages of EBV latency and how does gene expression change between them?
- latency III has lots of gene expression - EBNAs, EBERs, LMPs, BARTs and BHFR1s
- latency II has less expression - BARTs, EBER1+2 and LMPs
- latency I has the fewest genex expressed - EBNA1, EBER1+2 and BERT miRNAs
What kind of EBV latency is seen in cancer?
- different latency states associated with different cancers
- gastric carnionoma with II
- burkitts lymphoma with I
- differences are made more complicated by differences in miRNA expression
What mutations are seen in Burkitt’s lymphoma?
- chromosomal translocations resulting in c-myc oncogene activation
- can occur due to EBV among other mechanisms
What is Burkitt’s lymphoma?
- non-Hodgkin’s B cell lympoma
- tumours seen in EBV latency
- EBV proteins can prevent apoptosis of cells with c-myc overexpression
What is nasopharangeal carcinoma?
- epithelial tumour associated with EBV latency
- EBV almost always present in malignant cells
How is it thought thta EBV causes nasopharangeal cancer?
- infection of epithelial cells in the lab doesn’t immortalise them
- those with CDK/cyclin mutations can be immortalised
- cells may already need specific mutations prior to infection for EBV to cause cancer
- confirmed by the fact that EBV is usually found in high grade tumours not early staged ones
What is multiple sclerosis?
- chronic inflammatory and neurodegenerative CNS disease
- risk factors include genetics, obesity, smoking and EBV
What is some evidence of EBV association with multiple sclerosis ?
- increased MS risk in those with history of infectious mononucleosis
- decreased risk in seronegative people
- increased levels of EBV-specific antibodies in those with MS
- molecular mimcry between EBNA1 and CNS antigens
Describe the potential role of molecular mimicry in the relationship between EBV infection and MS
- antibodies from the CSF of MS patients recognise CNS proteins and EBNA1
- they have cross-reactivity that can
- immunisation of mive with EBNA1 peptides increased inflammation in the CNS
- only seen in 25% of MS patients so may be other cross-reactive antibodies
What factors hinder the development of an EBV vaccine?
- no appropriate animal model
- where to administer, how to administer, what to target?
Are there any EBV vaccines in clinical trials?
- 2 in phase 1
- mRNA vaccine that targets glycoproteins on the virus particle
- nanoparticle vaccine that targets surface protein gp350 on the virus and on virus infected cells
What is Kaposi’s sarcoma virus?
- gamme herpesvirus
- causes all Kaposi’s sarcomas
What cell types does KSHV infect?
many including B cells, epithelial cells, endothelial cells and DCs
What is Kaposi’s sarcoma?
- endothelial lineage tumours
- highly aggressive in immunosuppressed/AIDS
- KSHV latency in B cells and endothelial cells
What forms of Kaposi’s sarcoma virus are there?
- AIDS related
- latrogenic - severity is correlated with amount of immunosuppression given after transplants
- endemic - negative for HIV
- classic/sporadic
What diseases can Kaposi’s sarcoma virus cause?
- Kaposi’s sarcoma
- B cell lymphomas
- lymphoproliferative disorders
What kinds of treatments are used for KSHV diseases>
- bolstering the immune system ie using ART in HIV
- KS tumours can reoccur after chemotherapy
Does EBV replicate in the epithelial cells it initially transcytoses through?
- not sure
- but much harder to establish infection through apical surfaces than basal in the lab
- points towards infection of epithelial cells coming after B cell infection
