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MICR3320 > 9 - DNA Virus Replication > Flashcards

9 - DNA Virus Replication Flashcards

1
Q

dsDNA viruses

A
  • Herpesvirus
  • Papillomavirus
  • Polyomavirus
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2
Q

DNA viruses

A

Can cause productive lytic infections, cellular transformation, or latent infections

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3
Q

Lytic infection

A

The host cell dies as a result of producing progeny virions

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4
Q

Cellular transformation

A
  • Host cells begins to be transformed into a cancer cell
  • Cell becomes less responsive to physiological cues that regulate cell growth, differentiation, and death
  • Can be an evolutionary dead end for the virus, if no progeny virions are produced
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5
Q

Latent infection

A

Viral genome is mostly quiescent and no virions are produced for a period of
time that is much longer than the duration of a lytic cycle (ie. up to the lifetime of the host)

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6
Q

Virus replication sites

A
  • Cytoplasm: Most RNA viruses (besides retroviruses & orthomyxoviruses)
  • Nucleus: Most DNA viruses plus orthomyxoviruses (besides Poxviruses)
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7
Q

Viruses that replicate in both cytoplasm and nucleus

A
  • Retroviruses
  • Hepadnaviruses
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8
Q

mRNP

A

Mature mRNA in the nucleus is exported to the cytoplasm through the nuclear pores as a messenger ribonucleoprotein (mRNP) complex

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9
Q

What do baltimore class 1 (dsDNA) animal viruses rely on for geen expression

A

Host transcription machinery

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10
Q

Class 1 reliance on host transcription machinery

A
  • Most human cells do not divide
  • Viruses do not replicate well in quiescent cells
  • Viruses must induce host cell replication proteins (directly associated with virus size)
  • Virus-encoded early gene products regulate this, and put cells into synthesis (S) phase
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11
Q

Protein required for synthesis

A
  • DNA polymerase and accessory proteins
  • Origin binding protein, helicases
  • Exonucleases
  • Enzymes of nucleic acid metabolism (eg. Thymidine kinase)
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12
Q

Viral origins or replication (Ori)

A
  • AT-rich DNA sequence segments recognized by viral origin recognition proteins
  • Viral genomes may have up to 3 ori
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13
Q

dsDNA bi directional replication

A
  • Most nuclear dsDNA viruses replicate via this mechanism (in eukaryotic host cell nucleus)
  • DNA replication begins at ori
  • Topoisomerase unwinds dsDNA at ori
  • ssDNA-binding proteins cover the ssDNA created in the replication bundle
  • RNA primase synthesizes short RNA primers that are then used by the DNA polymerase to prime DNA synthesis
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14
Q

Polyomaviruses

A
  • Small DNA viruses that drive cells into S phase
  • Associated with post organ transplant kidney malfunction and merkel cell carcinoma
  • Smallest dsDNA viruses that infect animal cells
  • Non-enveloped spherical virions
  • 4- to 5-kbp circular dsDNA genome
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15
Q

Prototype polyomavirus

A

Simian vacuolating virus 40 (SV40)

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16
Q

SV40

A
  • Forces the host cell to express S phase genes and uses large T antigen and host proteins for genome replication
  • Host cells susceptible to infection by SV40 are typically
    in G0 prior to infection, which means that they do not
    contain nuclear DNA replication proteins
    -The virus must force the cell to express S phase genes in order to replicate its genome
  • Changes in gene expression are accomplished by the early nonstructural proteins large T antigen and small t antigen
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17
Q

SV40 large T and small t antigens

A

Multiple functions including manipulation of cell cycle and of apoptotic pathways

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18
Q

Rb (retinoblastoma) protein

A
  • Controls entry into S phase
  • Rb loss is associated with tumours (Rb is a tumour suppressor gene)
19
Q

Replication of SV40 genomes

A
  • Six large T antigen proteins form a hexamer, two hexamers bind ori in a head-to-head arrangement
  • The hexamers have helicase activity that facilitates melting of the DNA at the ori
  • DNA replication then proceeds bidirectionally, with each large T antigen hexamer progressing in opposite directions around the template (also known as θ replication)
20
Q

Crystal structure of a hexamer

A

Composed of large T antigen helicase domains and six Zn2+ atoms

21
Q

Initiation of SV40 replication by large T antigen

A
  • LT protein, T-Ag (the major early gene product of SV40) assembles at its binding
    site, ori
  • Intrinsic 3’-5’ helicase activity of LT unwinds DNA bi-directionally
  • Viral DNA synthesis occurs in 5’-3’ direction on both leading and lagging strands
  • Copied genome is assembled in capsid
  • Association of T-Ag with cellular p53 can be oncogenic
22
Q

SV40 early transcription

A

Proceeds unidirectionally terminating approximately halfway around the circular
genome

23
Q

SV40 alternative splicing

A
  • Major mechanism by which SV40 encodes so many different proteins
  • Results in three different mature early mRNAs that encode either small t antigen, large T antigen, or 17-kT protein
24
Q

SV40 early transcript products

A

Accessory molecules:
- Large T
- Small t
- 17-kT

25
Q

Late and very late transcript products

A

Structural proteins

26
Q

p53

A
  • Key protein regulator of apoptosis in response to DNA damage
  • Both DNA damage and viral infections activate p53
  • When p53 is activated, it becomes phosphorylated, which has two major effects
  • DNA viruses block p53 in order to prevent apoptosis and enable phosphorylation of pRB
27
Q

Two major effects of phosphorylated p53

A
  • Stimulates cells to undergo apoptosis
  • Prevents the pRB protein from becoming phosphorylated (if phosphorylated it would detach from E2F and transcription would proceed)
28
Q

Why do dsRNA viruses prevent or delay cellular apoptosis

A

Provides the virus with sufficient time to complete its replication cycle while enabling phosphorylation of pRB forces the host cell past the G1 checkpoint

29
Q

Large T antigen

A
  • Large T antigen interacts with pRB, preventing pRB from interacting with E2F transcription factors and
    thus de-repressing S phase genes.
  • The large T antigen also interacts with p53, which
    prevents p53 from stimulating apoptosis.
30
Q

Small t antigen

A

Interacts with the PP2A (phosphatase) complex and inhibits its activity, thereby preventing repression of S phase genes

31
Q

Polyoma virus JC

A
  • Can result in a fatal demyelinating disease of the CNS
  • Progressive multifocal leukoencephalopathy (PML) in which oligodendrocytes are destroyed
  • Can remain latent after infection and be reactivated
  • B lymphocytes principal carries of JCV DNA
32
Q

HPV

A
  • Reproduction cycle causes warts and leading causes of cervical cancer
  • Detected via pap smear
  • Gardasil vaccine prevents against most common forms
  • Spherical virions with circular dsDNA genome 6–8.5 kbp
33
Q

HPV replication cycle

A
  • Tied closely to differentiation status of host cell
  • Infect stratified squamous epithelia (found in skin)
  • Can only infect the living basal cell layer, meaning that an injury is necessary to allow the virion to bypass the upper layers of the epithelium
  • The earliest genes are expressed in the lower layers of the epithelium, whereas the later genes are expressed in the more distal layer
34
Q

HPV replication in stratified epithelium

A
  • The cells in the two lowest layers of the stratified epithelium are actively reproducing, thus providing DNA replication proteins to the virus
  • The remainder of the epithelium consists of differentiated cells that are not regularly dividing as they are pushed toward the distal parts of the stratified epithelium
  • In order to accomplish vegetative genome replication the virus must force the quiescent host cells in the
    midzone to express host DNA replication proteins (E6 and E7)
35
Q

E6

A

Covalently modifies the p53 protein, targeting it for degradation, thereby preventing p53-triggered apoptosis.

36
Q

E7

A
  • Binds to pRB so that pRB cannot bind to E2F transcription factors
  • Consequentially, the E2F transcription factors no longer repress the expression of DNA replication S phase proteins.
37
Q

HPV 1, 2, 4 and 7

A

Common warts

38
Q

HPV 1, 2, 4, 60 and 63

A

Plantar warts

39
Q

HPV 6, 11

A

Associated with genital, oral and laryngeal warts

40
Q

High risk HPV subtypes

A

HPV 16 and HPV 18

41
Q

Poxviruses

A
  • Largest dsDNA viruses that infect humans
  • Causes smallpox
  • Linear genome composed of 194 kbp of dsDNA with inverted terminal repeats that form covalently closed hairpin termini
  • Replicate in cytoplasm not nucleus, therefore need virally encoded RNA polymerase, transcription factors, and DNA replication proteins, likely contributing to the large poxvirus genomes
42
Q

Poxvirus structure

A
  • Enveloped, brick-shaped or ovoid virion, 220-450 nm long and 140-260 nm wide.
  • The surface membrane
    displays surface tubules or surface filaments
43
Q

Two distinct infectious virus particles of poxvirus

A
  • the intracellular mature virus (IMV)
  • The extracellular enveloped virus (EEV)
44
Q

Vaccinia growth factor activity

A
  • Vaccinia growth factor (VGF) mimics cellular epidermal growth factor
  • Binds to cellular epidermal growth factor receptors and triggers cells to enter the cell cycle and proliferate

MICR3320 (14 decks)

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