Herpesvirus Flashcards
What is herpesvirus?
- family of dsDNA viruses
- infect a wide range of species
- 8 cause disease in humans some life theratening
What is the structure of a herpesvirus particle?
- core contains a genome
- this is surrounded by a proteinaceous core which is surrounded by a complex icosahedral capsid
- a layer of tegument proteins resides outside the capsid
- envelope on the outside
What is the tegument?
- protein filled region
- when the virus attaches all the tegument proteins are released into the cell and can begin to have effects on the cell immediately after entry
What are the 2 herpes lifecycles?
- lytic replication involves the production of infectious virions, cell destruction and transmission
- latent infection allows virus to persist in cells indefinitely without producing many proteins
What are the 3 families of herpesvirus?
- alpha
- beta
- gamma
What are the characteristics of alpha herpesviruses? Give an example of one
- wide host range
- spread rapidly and cause efficient cell death in culture
- latently infects sensory ganglia
- e.g. HSV1/2
What are the characteristics of Beta herpesviruses? Give an example of one
- more limited host range
- slow cell to cell spread
- CMV
What are the characteristics of Gamma herpesviruses? Give an example of one
- most limited host range
- latently infect B or T cells
- EBV
What is HSV1?
- herpes simplex virus 1
- alpha herpes virus
- causes encephalitis and necorsis of the temporal lobe
Describe the genome of a herpes simplex virus
- composed of 2 covalently linked segments flanked by inverted repeats
- short and long segments
- repeats allow rearrangements of the regions into 4 different isomers
- 80 gene products 40 of which arent essential for replication
- lots of unspliced genes
- very complex genome
Where do herpes simplex viruses replicate when in lytic life cycles?
- nucleus of epithelial cells
- infectious virions are produced and cell destruction occurs
Describe the latent stage of a herpes virus infection
- reversible and non-productive
- infects immune privileged sensory ganglia
- can be life long
- to maintain a latent state the virus must evade host responses and limit its gene expression
Describe the lytic replication of herpes simplex virus
- attachment, fusion and release of tegument into the cell
- nucleocapsid enters the nucleus via microtubule transport and releases the viral DNA
- genome is replicated by the rolling circle method of replication
- then gets enveloped and released
How does herpes simplex virus enter the host cell?
- interaction of viral glycoproteins with host cell receptors
- gB and gC bind cell surface proteoglycans
- gD binds further herpes entry mediators to stabilise attachment
- pH dependent fusion of the viral envelope with the plasma membrane
How are herpes simplex virus genes expressed during lytic infection?
- tightly reagulated
- IE, E and L genes expressed in a temporal fashion where the expression of the previous set is required for expression of the nect
- interrupting one stage means the later ones arent expressed
What do HSV IE, E and L genes encode for in lytic gene expression?
- intermediate early is involved in the expression of viral genes
- early is involved in DNA metabolism and replication
- late is involved in assembly and encodes structural proteins
How are the herpes IE gene expression initiated?
- transcription initiation is due to the recruitment of cellular factors to IE promoters
- this is enhanced by VP16 in the tegument that recruits transcription factors and pol II to start transcription of IE genes
Describe HSV early gene expression
- replication occurs in replication compartments formed in the nucleus
- 7 E genes are essential for genome replication
- origin binding, DNA binding, helicase and polymerase important
What are the specific roles of the IE proteins of herpes virus?
- ICP0 allows transcription of early promoters
- ICP22 enhances ICP0 expression
- provide an environment conducive to viral genome synthesis
- stabilise viral mRNA to enhance translation
- can also affect MHC I presentation on cell surfaces
How is HSV genome replication initiated?
- binds to 1 of 3 origins of replication causing a bend in the DNA that forms a stem-loop and unwinds the DNA
- helicase/primase complex binds to ssDNA and synthesises RNA primers
- virla polymerase binds these and starts DNA synthesis
What is a rolling circle intermediate in HSV1 replication?
- circular replication structure is nicked after initiation to form a rolling circle
- replication forms long strands of viral progeny with multiple copies wound like a spool of ribbon
- cleaved at packaging sites to form single DNA genomes which are then packaged into virions
How is the HSV assembled after replication?
procapsid is formed around scaffold proteins which then get degraded to form an empty capsid for the genome to be packaged into
How does the assembled HSC capsid exit the host cell nucleus?
- too big for a nuclear pore so must bud through the membrane
- associates with the inner membrane by breaking through the nuclear lamina and buds into the perinuclear space - gains an envelope here
- its envelope then fuses with the outer nuclear membrane and exits into the cytoplasm
How and where does virion maturation of herpes virus occur?
- in the cytoplasm
- mature capsids associate with tegument proteins and bud into Golgi-derived vesicles that contain the glycoproteins produced during transcription
- second envelopment takes place here - unique double-envelopment process
- can alternatively recover memrbanes from the surface of the cell on its way out
What kinds of proteins can be found n the HSV tegument? give 4 example
- those important in initial infection
- VP16 associates with host cell proteins such as TFs to activate IE genes
- VHS (virion host shut off) degrades host mRNA
- ICP0 disrupts PML bodies and allows transcription of early gene promoters
- others interact with microtubules to facilitate virion transport to the nucleus
What are PML bodies?
- nuclear foci containing cellular proteins involved in transcription, DNA repair and apoptosis
- stored in the nucleus to be readily available to associate with viral DNA and restrict its expression
Where do herpes viruses travel to to become latent?
- enter the sensory neuronal axons
- migrate along the axon to the cell body of neuronal ganglions in the CNS
- during this migration most of the tegument proteins are lost
Why is loss of the tegument proteins important in herpes virus latency?
- no activation of IE genes from the lytic cycle can occur
- viral genomes become associated with methylated host histones to further repress transcription
In herpes virus latency, all transcription is silent apart from the expression of what?
- LAT
- keeps the genome silent and avoids host immune surveillance
- can be processed into 4 miRNAs that prevent the expression of lytic regulatory proteins and limit cytotoxic effects in doing so
How does herpes virus reactivate from latency?
- latent episome must reorganise its chromatin to ensure levels of IE gene expression are sufficient to overcome virus-encoded miRNAs
- nuclear accumulation of viral VP16
- demethylation of histones
- mature virions are produced and transport to axonal terminuses where they mature and release
What kind of stimuli can cause herpes virus to reactivate from latency?
- poorly understood
- physical stresses such as illness and exposure to UV light
- leads to demethylation of histones associated with viral DNA
What is Varicella Zoster virus?
- alpha herpes virus that causes chicken pox or shingles
Describe the basic life cycle of Varicella zoster virus
- enters mucosal epithelium
- spread to the tonsils and other lymphoid organs where it encounters and infects T cells
- establishes latency as in HSV-1
- reactivation from latency allows a second phase of replication in the skin
Are there vaccines for herpesviruses?
- live attenuated vaccine for chicken pox is 70-90% effective
- vaccines for HSV-1, EBV etc are in development
What kind of antiviral drugs are there for herpes viruses?
- nucleoside analouges such as Acyclovir
- helicase-primase inhibitors
How do nucleoside analogues (Acyclovir) work against herpes virus?
- analogues get phosphorylated by viral proteins and incorporated into viral DNA
- prevents chain elongation by pol and leads to cell death
- resistance is occuring
How do helicase-primase inhibitors against herpes virus work?
- inhibit the enzymes in the helicase-primase complex
- stops it from forming properly
- some can enhance DNA binding so much that the complex can’t move along the DNA
