9. The Pathogenicity of Viruses - Herpes virus

Question 1

How many types of herpes virus are known?

Answer 1

Two:

1. HSV-1
2. HSV-2

Question 2

Which type of HSV most often affects the mouth and which type affects the genitals?

Answer 2

HSV-1: oral infections

HSV-2: genitals.

Question 3

Which parts of the body can be affected by herpes?

Answer 3

Genitalia and mouth are most often infected however fingers, eyes and the brain have also been infected by the virus.

Question 4

What symptoms are associated with HSV infection?

Answer 4

Blistering and ulcers at the site of infection. The first outbreak of infection could also be accompanied by fever, muscle pains, swollen lymph nodes and headaches

Question 5

Describe the genome of the HSV.

Answer 5

Large double stranded DNA molecule with the ability to code for over 100 different polypeptides.

DNA surrounded by caspid.

Question 6

Describe the process of attachment of the HSV to the host cell.

Answer 6

The HSV binds to host cell GLYCOSAMINOGLYCANS (GAGS) mediated by the glycoproteins gC and gB.

The glycoprotein gD is then able to bind to its host cell surface receptors including (1) nectins, (2) “herpes virus entry mediator” (HVEM) and (3) 3-O-sulphated heparan sulphate (3-OS HS)

Question 7

How does the HSV enter the host cell once attachment has occured?

Answer 7

Fusion of plasma membrane:

Binding of gD to its host cell receptors results in a change in its conformation and that of glycoproteins gH and gL which ultimately result in the activation of gB which enables fusion of the virus and host cell membranes to incorporate the viral caspid into the cell

Calcium seems to be an important component of HSV entry however its exact role is not yet defined.

HSV has also been known to enter via endocytosis.

Question 8

Where is the site of replication of the HSV?

Answer 8

The nucleus

Question 9

How does the HSV capsids migrate to the nucleus upon entry?

Answer 9

HSV capsids migrate ot the nuclear pore along the microtubule network by the motor protein dynein.

Question 10

How is the HSV genome released from the caspid?

Answer 10

This process is not fully understood however previous studies have shown that empty caspids accumulate at the nuclear pores suggesting the genome is released from the capsid without its dissolution directly into the nucleus.

Question 11

What happens to the HSV ds DNA once it enters the nucleus?

Answer 11

Circulisation by which the viral DNA attaches together at its ends to form a circle.

Question 12

Describe the process of transcription of the HSV genome.

Answer 12

Transcription of the HSV genes occurs in the nucleus facilitated by host machinery - RNA polymerase II. Alpha genes are first transcribed and translated into their protein products followed by beta and gamma genes.

Question 13

Describe the process of translation of alpha, beta and gamma HSV mRNA.

Answer 13

Translation occurs in the same way as host cell mRNA using host machinery.

Question 14

How does the HSV ensure the preferential translation of its own mRNA over host mRNA?

Answer 14

1. HSV inhibits host transcription.
2. HSV inhibits host mRNA splicing
3. HSV degrades host mRNA
4. HSV enhances translation of its own mRNA by interacting with host translation factors.

Question 15

What is the role of alpha, beta and gamma proteins?

Answer 15

Alpha proteins are required for priming the cell in preparation for further viral gene expression. Beta proteins are involved in viral genome replication and beta and gamma proteins are associated with the production of viral structural proteins including capsid proteins and HSV envelope proteins.

Question 16

After translation, where do the viral envelope proteins go?

Answer 16

HSV envelope proteins enter the endoplasmic reticulum post translation and proceed to become incorporated into the nuclear membrane.

Question 17

What is known about HSV replication?

Answer 17

It occurs in the nucleus facilitated by beta proteins however not much is known regarding the mechanism of replication. One theory proposes that DNA replicates by a rolling circle mechanism where end to end copies of the HSV genome form which are then cut and packaged into individual capsids.

Question 18

How does HSV gain entry into the body?

Answer 18

The virus must come into contact with mucosal surfaces or abraded skin.

Question 19

How does the HSV ensure the preferential translation of its own mRNA over host mRNA?

Answer 19

1. HSV inhibits host transcription.
2. HSV inhibits host mRNA splicing
3. HSV VHS (virion host shutoff) protein degrades host mRNA
4. HSV enhances translation of its own mRNA by interacting with host translation factors.

Question 20

Describe the process of the release of HSV from the cell once caspids are formed in the nucleus.

Answer 20

Capsids bud off from the nuclear membrane to form its viral envelope. HSV copies then enter the ER to bud off again to the cytoplasm surrounded by a second plasma membrane. This outer plasma membrane then fuses with host cell membrane to release the HSV out of the cell.

Question 21

How is HSV transmitted?

Answer 21

Intimate personal contact between seronegative and someone excreting HSV.

Question 22

How does HSV establish a latent infection?

Answer 22

HSV is transported to dorsal root neural ganglia where they remain latent due to a silencing of the genome by the LAT transcript. Thus host cells remain unaffected by the virus allowing for a reservoir to be established.

Question 23

What two complications may arise of HSV transport to ganglia?

Answer 23

Replication in dorsal root ganglia can infrequently result in life-threatening CNS infection.

HSV is capable of migrating beyond dorsal root ganglia and developing into a systemic infection

Question 24

What is the effect of viral invasion on host cells?

Answer 24

Viral invasion causes ballooning of cells, condensed chromatin, degeneration of cellular nuclei, loss of intact plasma membrane all combining to form multinucleated giant cells which eventually lyse due to a viral mediated cell death, leading to inflammation which causes further damage.

Question 25

How does HSV evade the immune response?

Answer 25

1. HSV effectively ‘hides’ in neurons during latency as neurons do not divide, thus avoiding complete replication. Silencing of the genome also prevents measurable antigen production.
2. HSV inhibits the host cell immune response such as IFN or protein kinase R responses
3. ICP-47 protein of HSV blocks the TAP transporter associated with transport of viral antigens to the endoplasmic reticulum where they would be combined with MHC class I for expression. Therefore without antigen presentation cytotoxic t cells cannot kill the infected cell.

Question 26

How do HSV viruses come out of a latent phase?

Answer 26

During the latent phase, the ICP4 gene is bound to the ‘human repressor element silencing transcription factor (REST’ protein thus preventing transcription of ICP4, and thus transcription of other viral genes of the lytic cycle. Other proteins such as ICP0 which are released in cases of illness or emotional and physical stress are capable of reversing this inhibition and thus causing the reactivation of the virus.