Lecture 18 - Herpesviruses Flashcards
Passive immune evasion strategies of persistent infections 1) 2) 3) 4)
1) Cell tropism is nonreplicating cells
2) Replicates in sites not exposed to the immune system (blood brain barrier, eye, luminal surface of ducts)
3) Replicates in MHC negative cells (such as neurons)
4) Can spread by cell-cell fusion
Active immune evasion strategies of persistent infections 1) 2) 3) 4) 5) 6)
1) Limit expression of viral genes
2) Non-cytopathic infection (DNA genome integration)
3) Blockade of specific immune defences (block MHC, IFN, decoy cytokine receptors)
4) Blockade of apoptosis mechanisms
5) Rapid genetic evolution
6) Immunosuppressive, anergic epitopes
Anergy
When an epitope doesn’t elicit an immune response
Latent infection
Persisting infection with long periods without any detectable infectious virus or disease
How many herpesviruses lead to latent infection?
All
Breadth of species that can be infected by herpesviruses
Virtually all species
Structure of herpesvirus virion 1) 2) 3) 4) 5)
1) gB, gN glycoproteins on envelope
2) Enveloped
3) Tegument
4) Nucleocapsid
5) Circular dsDNA genome
Number of herpesviruses establishing life-long latency in humans
Eight
Broad types of herpesviruses 1) 2) 3)
1) Alphaherpesviruses
2) Betaherpesviruses
3) Gammaherpesviruses
Alphaherpesviruses 1) 2)
1) Herpes simplex (HSV-1 and
2) Oropharyngeal and genital infections
2) Varicella-zoster virus Chickenpox and shingles
Betaherpesviruses 1) 2)
1) Cytomegalovirus Mild fever Pneumonia, chorioretinitis in immunocompromised patients
2) Human herpesvirus 6 (HHV-6) Mild rash in infants (roseola infantum)
Gammaherpesviruses 1) 2)
1) Epstein-Barr virus Infectious mononucleosis Burkitt’s lymphoma Nasopharyngeal carcinoma Immunodeficiency-related lymphoproliferative disease
2) Kaposi sarcoma virus (HHV-8)
Where are alphaherpesviruses persistent?
In neurons
Where are betaherpesviruses persistent?
Maybe in monocytes or secretory glands
Where are gammaherpesviruses persistent?
In lymphocytes
Length of herpesvirus genomes
120-240kb
Number of proteins that herpesviruses encode
Normally around 80 proteins
Common early genes for herpesviruses
Enzymes (HSV thymidine kinase) and regulatory genes (HSV host shut-off gene product)
What does HSV produce during latency?
Latency Associated Transcripts (LATs).
What does EBV produce during latency?
EBNA 1-6 proteins
HSV1 prevalence
70-90% adults seropositive
HSV2 prevalence
20-60% adults seropositive
CMV prevalence
40-100% prevalence
EBV prevalence
90% adults seropositive
How do herpesvirus genomes persist in cells?
As a circular, non-integrated DNA (episome)
EBV genome origins of replication 1) 2)
1) Ori-P (Origin of plasmid maintenance) - Used to replicate genome during latent infection of dividing B cells
2) Ori-Lyt - Used to replicate genome during lytic infection
Ori-P
EBV origin of plasmid maintenance. Used to replicate EBV genome during latent infection of dividing B cells. Binding site of EBNA-1 protein (a latent gene product).
HSV genome origins of replication.
Has both Ori-P and Ori-Lyt, which are both inactive during latency, and both active during lytic infection.
How do herpesviruses replicate their genomes?
Fork replication, rolling circle.
Rolling circle replication
How are concatemers formed during herpesvirus genome replication?
ssDNA from rolling replication has discontinous strand formed on it.
EBV Ori-P driven infection
Latent replication in replicating B cells. Needs EBNA-a
EBV Ori-L driven infection
Active, lytic infection
Why doesn’t HSV need to express latent proteins, as EBV does?
HSV lies latent in non-replicating cells (neurons). Therefore, the episome won’t be diluted out with replication.
Number of HSV infections that are asymptomatic
85-90%
Number of HSV infections that result in lesions
10-15%
Number of HSV infections that enter blood and distant organs (EG: brain)
Under 1%
HSV CNS disease 1) 2) 3) 4)
1) Very rare (1-3000 cases per year)
2) Most common during disseminated infection of a newborn
3) 70% mortality rate. Under 2.5% achieve normal neurological function after infection.
4) Diagnosed by PCR of CSF, confirmed by viral culture.
Where on the lip does HSV-1 normally recur?
Mucocutaneous junction
Dorsal root ganglia that HSV will be latent in if initial infection is of the lip
Trigeminal ganglia
Dorsal root ganglia that HSV will be latent in if initial infection is of the genitals
Sacral ganglia
Size of HSV latent genome
150kb
Number of people who harbour latent HSV genome
20%
Number of HSV episomes per cell
10-100’s
Size of HSV LATs
~2kb
Type of axonal transport used by re-emerging HSV
Anterograde transport
LATs 1) 2) 3)
1) Stable, non-translated HSV RNA transcripts 2) ~2kb 3) Processed into viRNAs
Potential role of LATs
Suppress apoptosis, to maintain latency
How is primary viremia of VZV spread?
In DCs
How is secondary viremia of VZV spread?
In T lymphocytes
Timeline of VZV infection
Day 0 - Infection of conjunctiva and/or mucosa of URT - Viral replication in regional lymph nodes Day 4-6 - Primary viremia in bloodstream (DC spread) - Further viral replication in liver and spleen - Secondary viremia (T cell spread) Day 10 - Appearance of infectious vesicular rash
Most effective response to herpesvirus infections
T cell response
Where does VZV reemerge as shingles?
The dermatome where the virus initially infected
How can shingles be treated?
Acyclovir or other antivirals. Passive VZV MABs
Demographic at risk of shingles
Elderly (associated with immune decline). Children under 5 (from incomplete T cell immunity)
Human VZV vaccine 1) 2) 3)
1) Live attenuated 2) Recommended for all seropositive children after 12 months of age, booster at 10 years 3) Recommended for those at risk - teachers, health care workers
How is EBV transmitted?
Direct contact with infected saliva with oropharynx
Where does EBV-1 predominate?
Australia, Europe, USA
Where is EBV-2 found?
EBV-1 and -2 are equally prevalent in Africa
Where does EBV establish a productive infection?
Epithelial cells of the salivary glands and oropharynx
Site of EBV latency
B cells
What might EBV cause in transplant recipients?
B-lymphoproliferative disease
Is EBV initial infection lytic?
Yes
Does primary EBV cause a large immune response?
Yes
EBV proteins expressed during latency 1) 2)
1) Epstein-Barr virus Nuclear Antigens (EBNA). 6 Of these proteins. 2) Latent membrane proteins (LMP). 2 of these.
Protein involved in replication of EBV genome
EBNA-1
Three types of EBV latency
1) 9 latent antigens expressed 2) 3 latent antigens expressed 3) Only EBNA-1 expressed during latency
Disease associated with type 1 EBV latency
B-lymphoproliferative disease
Disease associated with type 2 EBV latency
Hodgkins disease
Disease associated with type 3 EBV latency
Burkitts lymphoma
Type of EBV mRNA that 90% of adults have in B cells
EBV LMP2a mRNA present in memory B cells
Malignancies associated with EBV reactivation
Hodgkins lymphoma, Burkitts lumphoma, nasopharyngeal carcinoma
What can congenital CMV infection lead to?
Deafness, chorioretinitis, microencephaly
Leading infectious cause of stillbirth
CMV
How does CMV infect a foetus?
~30% chance of crossing placenta form mother to foetus
