Viruses

Question 1

How are viruses different from cellular life?

Answer 1

Two Major Themes:
• They are not cellular life and, unlike cellular life viruses have not evolved from a single common
ancestor
• Viruses are a ‘collection’ of highly genetically diverse
classes, unrelated beyond certain general properties

Question 2

Possible viral genomes

Answer 2

DS DNA
SS DNA

DNA can be linear, circular or gapped

DS RNA
-SS RNA
+SSRNA

RNA can be segmented or non segmented (monopartite

Question 3

Why do viruses not meet the criteria for life?

Answer 3

2. Viruses are considered chemical assemblies and molecular nanomachines because TO to replicate, virions must enter cells, and they are absolutely dependent on at least some cellular factors and on

cellular metabolic energy
• Viruses are obligate intracellular parasites
• Have co-evolved to very efficiently exploit many host cellular processes for their own replication

Question 4

Two phases in virus lifecycle

Answer 4

1. VIRION PHASE: EXTRACELLULAR PHASE
   - A virion is a single infectious particle
   - All the parts of the virion are assembled inside host cell guided by the virus’ genome
   
   • Newly formed virions can exit the cell
   • Their extracellular phase involves them carrying and protecting the genome from cell to cell - they are inert carriers of nucleic acid genome, they cannot replicate and perform metabolism alone
2. INFECTED CELL
   
   • Once virion enters host cell, it can mani
     pulate host cell machinery to make new things that come together to make new virions
     The infected host cell essentially is the virus in that its producing all the new virions (philosophical idea, not always agreed upon)

Question 5

Why study viruses?

Answer 5

Viruses are everywhere
They can infect everything
We carry viral genomes in our genetic material - there are viral DNA sequences in our bloodstream

Question 6

Do viruses always make you sick?

Answer 6

• You carry many viruses as a healthy
individual…
• Most viruses do not cause disease in the
host
• The majority of viruses that infect us have
no impact on health
• Largely due to ‘healthy’ immune system
However, when there is immunosuppression, these viruses become a problem

Question 7

How have viruses shaped human evolution?

Answer 7

Our viral genome contains DNA from retroviruses - the DNA from retroviruses is referred to as endogenous retroviral elements
These endogenous retroviral elements encoded for cell fusion proteins and are thought to be responsible for the development of multicellular organs such as the placenta

Question 8

How can viruses be used for good?

Answer 8

Viral Gene Therapy:
- If viruses use nucleus for replication (especially seen in retroviruses), they’re good at delivering nucleic acid into the nucleus
- Lentiviruses are used (they’re a type of retrovirus that is genetically modified and have genes put into them to transfect cells for research and therapy
Oncolytic virotherapy:
- Viruses that are good at infecting and killing tumour cells
- They replicate inside the tumour cells and burst the cell
- Valuable for cancer therapy
Phage therapy:
- Used against drug-resistant bacteria
- Phage can infect bacteria and cause them to lyse
There are a huge number and variety of phage that are likely to be able to target every existing bacteria

Question 9

What have viruses taught us about humans

Answer 9

• Viruses are intracellular parasites:
- Every solution they come up with to counter the host tells us something about the host
• Viruses have coevolved to very efficiently exploit cellular process for their own replication
By examining how viruses exploit/modify cellular processes, we cam ‘decipher’ complex pathways in the host
Viruses have helped us to gain an Understanding of molecular/cell biology gene splicing, immune signaling, DNA replication, protein synthesis, vesicular trafficking

Question 10

What properties does a virus have

Answer 10

Small

Do not grow, are assembled de-novo from viral components synthesized by host cell

Question 11

How are viruses assembled?

Answer 11

Viruses require cells for assembly - they cannot grow in broth
Virus infects cell, viral components dissociate and genome is released. No new production of virus at this stage called eclipse phase.
Genome is replicated and viral proteins are produced. The replicated genome and newly synthesized viral proteins self-assemble to form viral particles. Here, is the burst phase, where we get a large production of virions per infected cell.
Virions are released from host cells via lysis or budding

Question 12

What is the general structure of virions?

Answer 12

They have:
1. Nucleic acid (genome),
• DNA or RNA NOT BOTH
Genome is surrounded by protective protein coat: Capsid
•Capsid is formed by selfassembly of capsomere subunits
The structure of capsid + nucleic acid is called nucleocapsid
Naked virus have nucleocapsid only
Enveloped virus has a lipid envelope which is taken from the host as the virus buds
Virus always have surface proteins to attach to target cell
• It can be on the capsid if virus is naked
It can be a glycoprotein embedded in the lipid envelope is virus is enveloped

Question 13

Other than envelopes, what are the three structural forms of a virus

Answer 13

Spherical: with icosahedral ordered symmetry
• formed by repeating units of protein
• A regular polyhedron with 20 triangular faces
2. Helical:
Rod shaped coat
• Formed by multiple repeating copies of protein coated onto the genome , which interact with each other to form a Hollow tube, like a spiral staircase
3. Complex: Large viruses; mixture of shapes, no consistent symmetry, such as bacteriophages

Question 14

What can we know about the virus by looking at its structure

Answer 14

Can make predictions on:
• Cell entry
• Disassembly, release of genome
• Assembly of virion
• Egress- viruses that are naked exit cell by cell lysis, viruses that are enveloped leave host cell by budding
-Stability/transmission:
• Enveloped — usually less environmentally
stable, envelope can dry out and is sensitive to chemicals and UV light
• Naked — more stable, resistant

Question 15

What are viruses defined as

Answer 15

Viruses can be defined as:
• Acellular infectious microbes, entirely dependent on host cell
• Reproduce & evolve only within cells
• obligate intracellular parasites
• without cells, viruses are inanimate complex organic matter
• Viral genome directs synthesis of viral components by commandeering host machinery
• Progeny particles (virions) formed by self-assembly from newly synthesized components
within host cell - viruses do not grow, do not divide
• Viruses lack genetic information encoding:
• machinery to generate metabolic energy, carbon metabolism
• machinery to generate membranes
• machinery for protein synthesis such as ribosomes
• All viruses (even giant viruses) lack a COMPLETE protein synthesis (ribosome) machinery
All viruses must be able to make mRNA, which is translated by host cell ribosomes
Thus, viruses are basically Parasites of host protein synthesis machinery

Question 16

General virus life cycle

Answer 16

• Virus bind to host cell receptor
  Virus is internalized into cell
  Genome and capsid dissociate, genome is released
  Genome is replicated, viral proteins produced by host ribosome
  Newly replicated genome and proteins come together form virion
  Virion exits cell via lysis or budding

Question 17

What makes a good receptor for a virus?

Answer 17

The receptor can be made from anything - it can be proteins, oligosaccharides, lipids ,and it can have an function - doesn’t matter
However, the receptor should be exposed to external surface so virus
Receptor binding facilitates recognition of host cell, viral entry into host cell, uncoating of genome

Question 18

Host Species tropism vs Tissue Tropism

Answer 18

Host tropism - bat and human may have the same receptor that the virus binds to but the virus that infects bats can’t bind to the human receptor as there are differences in the amino acid sequences of these receptors that prevents the viruses that infects bats from binding to human receptor with good affinity - however the virus can acquire genetic mutations that will enable it to bind to the human receptor
Tissue tropism - virus can only infect organs that express its receptor - if its receptor is found in the liver but not kidney - virus can only infect liver

Question 19

Transcription and Replication Viruses

Answer 19

• Once virus completes 2nd stage (penetration/disassembly/uncoating) and its genome is exposed in the cytoplasm of host cell, there is transcription of its nucleic acid into mRNA and replication (copying of its nucleic acid)
  
  • To fulfil these 2 processes, nucleic acid polymerases are required
    1. Transcription:
  • All viruses make some protein before their genome is replicated
  • To make protein, they must be able to produce mRNA that is recognised by host cell’s ribosomes as cellular (ribosomes must mistake the viral mRNA as cellular mRNA)
  • Ultimately the ribosomes can translate the mRNA into viral proteins - some of which feedback and activate replication
    2. Replication
  • New genome made using viral genome template
    Everything assembles and comes together

Question 20

Baltimore

Answer 20

7 classes

Grouped on basis of nature of nucleic acid genome and the mechanisms used to replicate genome and generate mRNA

Question 21

7 classes of Baltimore

Answer 21

DS DNA viruses - use DNA dependent polymerases for replication and transcription
SS DNA - converted into DS DNA and use DNA dependent DNA polymerase for replication and transcription
DS RNA - use RNA dependent RNA polymerases for replication and transcription
+SS RNA - use RNA dependent RNA polymerases for replication, +ssRNA = mRNA so +ssRNA is directly translated by cell ribosomes
-SSRNA - use RNA dependent RNA polymerases to convert into + SSRNA RNA - +ssRNA can be directly translated by host cell to produce proteins, and RNA dependent RNA polymerase uses +SSRNA as a template to produce more -SSRNA
Retroviruses - uses RNA dependent DNA polymerase reverse transcriptase to reverse transcribe their RNA into CDNA which is then integrated into genome and replicated and transcribed along with genome using DNA dependent polymerases
Hepadnoviruses - DS DNA gapped viruses - undergo cellular repair and then use RNA dependent DNA polymerase

Question 22

Class 1 DS DNA Virus example

Answer 22

Herpes Simplex Virus

Question 23

Herpes Simplex Replication and Transcription

Answer 23

Class I - dsDNA viruses:
Example: Herpes Simplex virus 1 (cold-sore virus)
- The virus binds to a specific surface receptor and penetrates through the membrane of the host cell
- It delivers its nucleocapsid into the cytoplasm
- The DNA genome uncoats and then enters the nucleus
- Its then circularises and associates with histone proteins in the form of nucleosomes - this condenses the DNA and produces viral chromosomes ; Most DNA viruses (not all) replicate in the nucleus because that’s where the cellular replication machinery is
- Once DNA is in the nucleus, transcription occurs
- DNA viruses have waves of gene expression which mediate different stages of the replication process; for the Herpes Simplex virus these are:
Ø Expression of Immediate Early (IE) genes
Ø Expression of Early (E) genes
Ø Expression of Late genes
One important protein that needs to be remembered is Viral protein VP16
- This protein is within the virion and is delivered to the nucleus together with the viral genome
- Its job is to recruit and stimulate the cellular DNA-dependent RNA Polymerase to transcribe the IE genes
- This generates mRNA from the set of IE genes that goes to the cytoplasm and is translated on ribosomes
- The IE gene proteins generated in the cytoplasm return to the nucleus
- These IE gene proteins include a number of transcriptional activators and when in the nucleus they interact with the genome again to stimulate E gene expression
- This leads to the production of viral DNA-dependent DNA polymerase which replicates the viral DNA genome
- The genome produced by replication is transcribed to make the Late genes
- The Late genes encode structural proteins that are involved in assembly of the virus

Question 24

RNA viruses

Answer 24

• Make RNA out of RNA ; only ever use RNA as genetic material
  
  • 2 classes: Class IV and Class V
  • Class IV are + ssRNA viruses and include SARS
  • Class V are - ssRNA viruses (lyssaviruses) and include measles, Rabies, Ebola
  • For transcription, they produce mRNA from RNA
  • For replication they copy the genomic RNA (gRNA) into a complementary anti gRNA which they use as a template to copy back the gRNA
  • Our cells can’t do transcription and replication in this way as we don’t have the right enzymes - thus these RNA viruses have to encode their own viral polymerases

Question 25

+ssrna viruses

Answer 25

+) ssRNA:

- Is mRNA 
- Called positive sense because it has the sequence that is translated to protein
- Can be translated immediately by ribosomes when the virus uncoats and exposes it in cytoplasm of host cell 
- Results in production of several proteins, including RDRPs which are required for copying of mRNA and replication of genome
- The structural proteins made are important in assembling new viruses 
- So for + ssRNA viruses, the nucleic acid alone is sufficient for infection (can strip away all the protein and artificially inject the RNA genome itself into host cells and they will make more protein, more genome and more viruses)

Question 26

-ss rna

Answer 26

• Opposite to + ssRNA, anti-sense (not the right sequence to make proteins)
  
  • To make protein from - ssRNA, it has to be copied back into + ssRNA (mRNA)
  • Cannot be translated immediately by ribosomes
  • Virion has to both encode RDRP in genome and carry the actual protein RDRP so that once the - ssRNA is delivered into cytoplasm, the RDRP can make mRNA which makes protein and more RDRP, enabling replication
    Structural proteins are also made to assemble new viruses

Question 27

Retroviruses

Answer 27

Retroviruses (Class VI):
- Have an RNA genome but reverse transcribe into DNA
- These are basically + ssRNA viruses but differ from the classical ones in that their + ssRNA is not used as mRNA
- Immediately after uncoating and exposure of the + ssRNA in the cytoplasm, the + ssRNA is converted to dsDNA by Reverse Transcriptase (RT) which is encoded and carried by the virus ; this action by RT occurs before any mRNA is made
- The dsDNA made goes into the nucleus and is inserted into the genome of the host by an enzyme called integrase (enzyme brought by the virus)
- Once this DNA is inserted into the genome, it’s called Provirus ; this DNA stays with the cell as long as the cell lives - if the cell divides, it will go across to the daughter cells as well
Normal cellular machinery is used to transcribe and replicate the viral DNA - cellular RNA Polymerase II makes mRNA which is converted into protein ; this mRNA is also basically the genome of the virus (because it’s a + ssRNA virus) so once enough of it is replicated, its packaged and assembled into new viruses

Question 28

Enveloped viruses

Answer 28

Enveloped viruses:

- Bud off the host cell, stealing the envelope from the host cell 
- Viral membrane proteins encoded in the viral genome that are produced within host cells resemble cellular signals that allow them to be delivered and embedded in particular membrane regions (like the plasma membrane)  
- The viral capsid interacts with these regions of the membrane and through a mechanism involving cellular processes and viral proteins, the budding off process occurs 
- The host cell stays in-tact and re-seals once virus has budded off (no damage)

Question 29

Naked viruses

Answer 29

Naked viruses:
- Once there is enough viruses within host cell, the cell bursts open and releases the non-enveloped viruses
Involves specific proteins called Viroporins made by the viruses when they’re ready to leave - these proteins are hydrophobic and insert themselves into the cell membrane and destabilises it causing cell lysis

Question 30

Types of viral infections

Answer 30

Acute infection:
Rapid onset of symptoms
Symptoms last for a brief period
- Resolution by immune system or death
Acute - EBOLA
Latent infection:
- Begins with an initial acute infection ; may have symptoms, may not
- Then it becomes quiescent but with repeated reactivation - periods where no virion is produced
- Virus is still present in these periods but the viral genome replication and synthesis of new virions occurs in very small quantities or not at all
- This allows for a productive infection later and allows for immune evasion in these periods
Persistent infection:
- Long-term infection
- Primary infection is not completely cleared by adaptive immune response - this can happen when replication of the virus occurs in some tissues such as in the CNS where there is limited immune surveillance to prevent inflammation
- Particles and genomes are produced continuously through the life of the host or can be sporadic
- There’s release of the virus without cell death (non-cytopathic; typical of enveloped viruses)
- Can lead to death

Question 31

Temperate bacteriophage

Answer 31

Infects bacteria, can enter into both a lytic and latent cycle

Question 32

Lytic and latent cycle

Answer 32

• Lytic bacteriophage only ever undergo the lytic cycle but temperate phage can undergo both lytic and lysogenic cycles

Lytic:
- Involves transcription, replication and assembly

Lysogenic Cycle (Latency Replication) - temperate phage

- DNA injected by phage integrates into the host chromosome - the phage DNA is then called prophage 
- There's no replication (it's quiescent/latent) ; 
- There might come a point where there is Genotoxic stress, starvation or overgrowth - when phage detects that there is something wrong with the cell and the bacterium, it re-enters lytic cycle and begins to replicate so it can go somewhere else and infect something else

Question 33

Transcriptional Programs

Answer 33

Lytic Transcriptional Program:
- Leads to lysis
Lysogenic Transcriptional Program:
- Leads to latency

Bacteriophage genome:
1. Left Operon (Lysogenic Genes)
- Encodes things like:
Ø integrase which puts the prophage into the host DNA)
Ø Repressor of the right operon promoter
2. Right Operon (Lytic Genes)
- Encodes:
Ø Proteins required for replication, lysis, assembly
Ø Repressor of the left operon promoter

Process:
- Phage genome enters cell and is transcribed
- Both of the repressors are made (transcribed by cellular RNA Polymerase)
One of the repressors binds first to operator sequences that regulate the promoters going in one direction

Question 34

Lysogenic

Answer 34

Lysogenic Pathway:

- Lambda repressor protein (CI) is expressed and binds first to the operator sequence on the right, thus inhibiting transcription of the lytic operon 
- Therefore, the polymerase only goes down the lysogenic path and transcribes more of the lysogenic genes 
- These genes encode the lambda repressor protein, so once they're transcribed, more of the repressor protein is produced and positively feeds back, further repressing the lytic genes and thus enhancing the lysogenic pathway

Question 35

Lytic

Answer 35

Lytic Pathway:

- Opposite thing happens 
- Cro repressor protein is expressed and binds first to the operator sequence on the left, thus inhibiting transcription of the lysogenic operon

Question 36

Are repressor actions reversible?

Answer 36

Yes
These repressor actions should be reversible:
- If in the lysogenic/latent cycle, should be able to switch to the lytic cycle
- DNA damage of the bacterium (through things like UV radiation) notifies phage that the bacteria is in trouble and so it should switch from lysogenic pathway to lytic pathway in order to replicate and go somewhere else
As a result there is activation of the SOS pathway (DNA damage pathway)
- One of the proteins involved in this is RecA (a protease) which continually degrades the lambda repressor protein of the lytic pathway
- Therefore there is predominant transcription of the lytic genes and thus production of the cro repressor which inhibits lysogenic pathway
New bacteriophage produced within the cell lyse the cell and goes to infect other bacteria

Question 37

Example of virus with latency transcriptional program

Answer 37

Mammalian virus that can undergo latent or lytic infection
Herpes Simplex Virus 1:
- Is transcriptionally regulated (2 possible programs, lytic or lysogenic)
- Can re-enter from latency to productive infection, given the right stimulus
- Initial infection is a productive infection where the virus infects epithelial cells in the mucosa, resulting in cold sores, inflammation and other symptoms
- Once more virus is produced as a result of the productive infection, these can enter peripheral nerves that innervate this region of the epithelial cells and traffic through these neurons to the cell body
- The viral DNA then enters the nucleus and it just stays there (no expression of the IE,E or Late genes (Lytic genes))
- Unlike many other mammalian viruses, the genome of HSV1 doesn’t integrate into host genome because it doesn’t need to ; its infecting neurons which don’t replicate or divide, so as long as the viral DNA is in the nucleus of the cell body, it’s made into chromatin because it has histones, and it will just sit there without doing anything
- However, there is a latency transcriptional program where you get a single RNA transcript called the latency associated transcript
- Antiviral mechanisms are ineffective so infected individuals are infected for life
It can reactivate under certain circumstances, causing the virus to move from neurons back to epithelial cells

Question 38

HSV1 Latency transcriptional program

Answer 38

• 2 things are required for a productive infection: genome needs to get into nucleus and VP16 which is needed to activate host RNA Polymerase (Pol II) to make the IE genes which activate the rest
  Host Cell Factor (HCF):
  
  • HCF needs to be in the nucleus because it is a co-factor of VP16
  • It’s involved in activating the host RNA Polymerase
  • In epithelial cells, HCF is in the nucleus (right place to interact with VP16 and the genome) but in neurons it’s in the cytoplasm
  • As HCF is not in the nucleus of neurons, it can’t interact with VP16 and there’s no production of IE proteins, meaning none of the subsequent gene waves

Process:

- HSV1 viral DNA is packaged up into chromatin 
- Chromatin can have active and inactive regions based on post-translational modification 
- A certain post-translational modification involves the nucleosomes compacting into very compact chromatin, meaning there's no transcription of these regions as the transcriptional machinery can't get in there 
- There are other modifications (acetylation) that open this compact chromatin up so transcription can occur 
- The lytic gene regions in neurons are inactive while the latent gene regions that encode the Latency associated transcript (LAT) are active and can be transcribed 
- LAT stops genome replication - it favours condensed chromatin structure where the replication genes are 
- At some point there can be reactivation (some kind of stressor can trigger productive infection so that the virus moves from the neurons to epithelial cells, causing disease symptoms to become visible)

Question 39

How do viruses cause disease

Answer 39

1. Cell death
   
   • Some viruses can cause cell death such as through lysis; these viruses are cytopathic and mainly include non-enveloped viruses but sometimes enveloped viruses too ; These viruses lyse cells through their replication and cause disease
   • Some viruses don’t lyse cells but they change the way cells function (e.g. rabies virus causes disease symptoms not by damaging the neurons but by affecting the way they work)
     2. Immunopathology
   • Over-aggressive response can come from adaptive immune response, mainly T-cells, when they attempt to eliminate the virus and cause damage to host tissues
   • It can also come from innate immune response, through the production of cytokines called interferons which normally induce an antiviral response to slow virus down ; when these become systemic they affect cells throughout the body and cause flu-like symptoms like fever
   • This is why many viral infections result in flu-like symptoms; these aren’t caused directly by the virus but actually by the innate immune system and interferons as they attempt to slow down the virus
     3. Immunosuppression:
   • Certain viruses like HIV infect immune cells and prevent their ability to deal with other diseases, therefore leading to secondary infections, opportunistic infections or the development of cancers etc.
     4. Oncogenesis
     Some viruses cause cancers

Question 40

Viruses that cause disease by cell lysis

Answer 40

Example: Poliovirus
- + ssRNA
- Non-enveloped, naked
- Leaves cells through lysis ; lyse the cells through Viroporins
- Most infections are asymptomatic or mild (helps virus maintain and spread)
- Mainly infects gut mucosal surfaces - cells here are good at regenerating so the virus lysing them isn’t too big of a problem and won’t cause severe symptoms
Problem is that sometimes the virus spreads through the blood and can even cross the blood brain barrier - cell lysis in the brain is much more serious because neurons are non-regenerative ; this is how you can get paralysis from polio infection

Question 41

Viruses that causes disease due to overactive immune response

Answer 41

Hepatitis B and Dengue fever

Question 42

Hepatis B

Answer 42

Example: Hepatitis B
- Is a Hepadnavirus (gapped double stranded DNA viruses)
- During infection, it expresses envelope proteins on the liver cells (hepatocytes) that it infects which can be recognised by T cells
- Upon recognition, T cells can induce apoptosis of the infected hepatocytes and produce cytokines that recruit other immune cells
This overall immune response can cause liver lesions that are characteristic of Hep B

Question 43

Dengue fever

Answer 43

Example: Dengue Haemorrhagic Fever

- Dengue comes from mosquitoes 
- + ssRNA virus 
- A primary infection tends to be asymptomatic or an acute febrile disease and is called break back fever 
- Secondary infection involves Antibody-dependent Enhancement (ADE) which can be really serious and result internal bleeding and haemorrhagic fever which is often fatal

Question 44

Antibody dependent enhancement

Answer 44

Antibody-dependent Enhancement (ADE)

- 1st (primary) infection by one serotype produces the typical adaptive immune response, activating B cells to produce antibodies and memory cells 
- In 2nd (secondary) infection by a different serotype of the virus, memory cells from primary infection against first serotype produce antibodies very rapidly; these antibodies bind to the virus but not in the right way because it's a different serotype and so there's no effective neutralisation 
- This results in the virus in the 2nd infection not being inactivated
- The virus is actually binding to cells through the antibodies which bind to Fc receptors on cells 
- Thus there is infection of cells, such as monocytes, that are not normally susceptible to dengue
- The viral load is then hugely increased 
- The infected cells, like monocytes, produce pro-inflammatory cytokines that stimulate cytokine production in T cells 
- There's a massive immune response which can cause plasma leakage and haemorrhage 
- Haemorrhagic fever is very rarely seen in primary infections by this virus but it's very common in secondary infections by a different serotype

Question 45

Oncogenesis

Answer 45

Oncogenesis:

- Transformation of cells into cancerous cells involves dysregulation of the cell cycle 
- Cell cycle in mammals is driven by mitotic signals that activate proteins called cyclins that act through CDKs and regulate proteins and transcription factors that drive the cycle forward 
- Proteins that drive the cell cycle and synthesis and replication of DNA can become oncogenic if they cause uncontrolled replication - the genes for these proteins are called proto-oncogenes  because they have a natural function but when dysregulated (if mutated or overexpressed) they become oncogenes and result in cancer 
- Tumour suppressor genes act at various checkpoints in the cycle to prevent inappropriate replication and are required to prevent cancer development

Question 46

How can viruses cause oncogenesis

Answer 46

Viruses can cause oncogenesis by activating cellular oncogenes, expressing their own oncogenes (e.g. Retroviruses), inactivating tumour suppressors

Question 47

Example of virus that causes oncogenesis

Answer 47

• All DNA viruses require something from the host cell that’s involved in DNA replication to drive their own replication
  
  • This means DNA viruses very often regulate the cell cycle - if they infect a resting cell (G0), they need to drive the cell cycle to the synthesis point (S) where the cell replicates because they need to replicate their own genome
  • One way these viruses drive the cell cycle is through inactivating tumour suppressor genes that normally stop the cycle from going forward
    Example: Retinoblastoma
  • Dysregulation of the Rb protein associated with several cancers
  • Rb protein’s key function is suppressing transcription factor E2F
  • During early phase of cell cycle or when the cell is resting (G0), E2F is blocked by Rb
  • Rb is not phosphorylated so it can bind to E2F and suppress it
  • When a mitogenic signal is received, CDKs (cyclin dependent kinases) are activated and phosphorylate Rb, releasing E2F
  • E2F binds to its promoters in the DNA and induce various mRNAs that are translated into specific proteins involved in mediating the progression of the cell from G1 phase into S phase (synthesis and replication)
  • DNA viruses can force host cells to go to S phase by manipulating Rb
    HPV:
  • Early genes encode proteins that sequester Rb, which drives the cell into S phase ; normally this isn’t a problem - the virus replicates and leaves the host cell
  • However, if the viral genome integrates into the cellular DNA, the regulation of these early genes is lost so there is constitutive expression of the early gene proteins like E7 that continue to sequester Rb
  • Consequently E2F is continuously active and host cells continue to proliferate, leading to cancer

Question 48

Can retroviruses cause oncogenesis?

Answer 48

yes, retroviruses can integrate into an oncogene - transducing retrovirus, or can integrate upstream of the oncogene - non-transducing retrovirus