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BIOL3017 - Molecular and structural basis for disease > Viruses > Flashcards

Viruses Flashcards

1
Q

What is the most common drug hypersensitivity reaction? how does it occur

A

Morbilliform drug eruption:
amoxicillin treatment for sore throat and fever +
Epstein Barr Virus infection (EBV, mononucleosis)

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2
Q

What is Epstein Barr Virus?

A

EBV causes Infectious Mononucleosis (IM) also known as glandular fever (kissing disease)

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3
Q

Explain the herpes life cycle

A

See diagram

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4
Q

What are the three phases of gene expression in herpes

A
  1. tegument proteins regulate production of mRNAs and proteins of 
IE immediate early genes; they
    -protect the virus against innate host immunity
    -promote transcription of early genes
  2. production of E early 
mRNAs / proteins; they
    - are involved in 
viral replication
  3. production of L late
 mRNAs / proteins; they
    are involved in 
virus assembly
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5
Q

Explain how herpes ans EBV illustrate the virus principle

A
  1. specific ways to get into the
host cells: attachment and virus entry
  2. Distinguish the virus’ genetic material
    Host interactions to establish chronic infection
    Expression of viral genes is often in phases
  3. Virus replication, assembly and release
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6
Q

Explain features of Herpes and EBV

A

dsDNA - Linear in acute, circular in latent phase
120-140kb
120-200nm, envelope, capsid
down-regulate pro-inflammatory responses and MHC-II
can infect B and T cells
widespread infection

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7
Q

Explain points of intervention within the general virus life cycle

A
  1. receptor binding (COVID)
  2. entry (COVID)
  3. mRNA function- Interferon > RNA breakdown
  4. DNA/RNA synthesis
  5. assembly - Protease (COVID)
  6. release - Neuraminidase (Influenza)
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8
Q

How does INFy orchestrate viral defense?

A

Type 1 interferon (IFNa - dentrites and IFNb - fibroblasts) produced by infected cells (autocrine and paracrine)
production of >300 gene products and stimulates:
T cells and NK cells produce type II INFy
INFy kills virus infected cells/cancer cells
autocrine - virus replocation in hibition, apoptosis
paracrine - up-regulation of MHC-1 and NK activation

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9
Q

Virus epidemic examples

A

SARS outbreak 2002/3 - 8,000 cases, 800 deaths nearly 10% fatality

Middle east (MERS): 2012/3 - 1,300 cases, 400 deaths; nearly 40% fatality

COVID19 - 75,000,000 cases, 6,900,000 deaths, 0.9% fatality

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10
Q

what does R0/ the R number mean? give examples

A

of individuals one sick person will infect

2 = HepC, Ebola, Influenza
4 = SARS, HIV
6 = Pox
10 = Mumps
18 = Measles

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11
Q

Explain the use of Dexamethasone in COVID-19

A

Corticosteroid
in UK - tested on hospitalised patients with COVID-19
benefits for critically ill patients -reduction in mortality by 1/3 for people on ventilators, 1/5 for people on oxygen

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12
Q

Give examples of different types of approved drugs for virus treatment

A

Nirmatrelvir and Ritonavir (Paxlovid, protease inhibitor)
Remdesivir (Veklury, nucleotide interfering with viral RNA replication)
Molnupiravir(Lagevrio, same as above)
Sotrovimab (Xevudy) is a “biological” – monoclonal antibody or mAb

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13
Q

Explain features of the drug Paxlovid (CHECK WHAT IT TREATS)

A

Convenience: orally bioavailable (50% in rats) (95% absorbed from GI)
Efficacy: reduced hospitaliasation and mortality
Mechanism: inhibits the cystine protease Mpro that helps cleave and mature chains of the viral protein
prevents transmission

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14
Q

what are proteases required for in virus infection

A

virus entry
endosomal release
cleave polyproteins

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15
Q

Describe features of the drug Sotrovimab

A

Monoclonal antibody
Recognises spike protein of virus
used to treat symptomatic acute covid-19 infection in 12 and above
overcome infection and prevent serious illness

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16
Q

What is a mAB?

A

Monoclonal antibody:
- Mouse (or other animal) challenged with an antigen
- produces cells that produce specific antibodies
-Cross these cells with an immortal / cancerous cell
- Each cell colony then produces a specific antibody, a clone

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17
Q

Neutralising SARS mAB

A

Source animal is human
Make a monoclonal antibody, as before
Test effectivity against antigen, here SARS spike protein
Spike receptor binding domain (RBD) targeted mAb neutralise the virus (Graham 2021)

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18
Q

What is a virus factory?

A

A compartment within an infected cell, made by the virus to protect it from degradation/host defences

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19
Q

Example of a virus that creates a virus factory

A

Coronaviridae (COVID), Pox, Herpes

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20
Q

Examples of cytoplasmic virus factories

A

Coronaviridae use double membrane vesicles (DMVs) 
in the cytoplasm where the dsRNA is produced
Poxvididae form a viruplasm for viral replication and assembly

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21
Q

Examples of nuclear virus factories

A

Herpesviridae formnuclear replication compartments(RCs) 
for viral DNA replication and late gene transcription

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22
Q

Examples of RNA viruses

A

Paramyxovirus (mumps & measles):
RNA-negative strand (mRNA complement)
linear ssRNA– genome, 15.3 kb
enveloped, size 150 nm

Mumps: infection of the ductal epithelium lading to Parotitis; the mumps virus can cross the brain blood barrier and infect ependymal cells
Paramyxovirus down-regulates innate immunity by interfering with interferon responses

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23
Q

Explain virus classification

A

How they look: capsid, envelope

Their genome:
This can be either DNA or RNA

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24
Q

Do Viruses violate the central Dogma?

A

YES

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25
Q

Virus classification by nuclear material (Baltimore classification)

A

double or single stranded DNA viruses
I- dsDNA: all mechanisms like DNA genomic host cell
II- ssDNA: convert to dsDNA first, then like host cell

double or single stranded RNA viruses
III - dsRNA: RNA used as template for mRNA
IV - ssRNA: a positive strand has the same orientation as mRNA;
requires synthesis of complementary RNA first;
mRNA is then synthesized from the complementary RNA strand
V - ssRNA: a negative strand is complementary to mRNA;
mRNA can be synthesized directly from the genome template

VI: RNA genome but dsDNA intermediate
VII: DNA genome but ssRNA intermediate

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26
Q

Examples of virus in the class 1 classification

A

dsDNA
use normal cellular mechanisms
Herpes, papilloma, pox

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27
Q

Examples of virus in the class 2 classification

A

ssDNA
Convert to dsDNA first
e.g. parvo

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28
Q

Examples of virus in the class 3 classification

A

dsRNA
use normal cellular mechanisms
e.g. reo, picobirna

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29
Q

Examples of virus in the class 4 classification

A

ssRNA+
must synthesise complementary strand 1st
e.g corona

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30
Q

Examples of virus in class 5 classification

A

ssRNA-
use the normal cellular mechanism
e.g. paramyxo, filo, orthomyxo

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31
Q

Examples of virus in class 6 classification

A

ssRNA+, DNA intermediate (retrovirus)
Convert their genome to DNA
e.g. HIV

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32
Q

Examples of viruses in class 7 classification

A

dsDNA, RNA intermediate
Use an RNA intermediate
e.g. hepadna

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33
Q

estimate of how many viruses on earth

A

10^31 (2000 known species)

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34
Q

Which Baltimore class of virus is most common

A

4

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35
Q

Influenza life cycle

A

Attached to silica acids on the membrane surface and on proteins
Internalised
Sheds Cathrin coated vesicle
Releases ribonucleoproteuin
Makes mRNA that are spliced to make proteins
RW

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36
Q

How does influenza enter cells

A

attachment
endocytosis
acidification of the endosome
pH induced conformational change of hemagglutinin (surface protein) - exposure of hydrophobic residues
Leads to loss of envelope and release of viral genome

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37
Q

Hemagglutinin features

A

active, virus form
trimeric membrane protein
bind glycosylated surface proteins on host membrane

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38
Q

Drugs targeting which proteins are being developed to target influenza

A

drugs against M1 and M2

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39
Q

Two external proteins of influenza

A

H=Hemagglutinin
glycosylated protein
binds to sialic-acid

N=Neuraminidase
hydrolyses sialic-acid glycosylation
active against Hemagglutinin as well as surface proteins

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40
Q

How is targeting neuraminidase a point of therapeutic intervention

A

N Allows virus to leave the cell - this is a step of therapeutic intervention e.i inhibition of N enzyme

41
Q

Examples of drugs that hinder virus release

A

Tamiflu (Oseltamivir) & Relenza (Zanamivir)
1. neuraminidase inhibitors
2. interfere with the release of the virus from the cell surface

42
Q

Number of hemagglutinin and neuraminidase types

A

H = Hemagglutinin, 16 known
N = Neuraminidase, 9 known
Recombination of RNA segments generation of new virus types

Segmental genome of 8 segments
New virus variants are created by changing segments

43
Q

Explain what classification of virus bacteria, plants and animals are primarily infected by

A

Bacteria infected by dsSNA viruses (primarily)
Plants infected by SSRNA viruses (primarily)
Animals are infected by all (but ssDNA) viruses

44
Q

Ebola virus disease (EVD) features

A

ssRNA virus
Large- not transmitted by air, need contact
Glycoprotein on surface
one of the worlds most virulent, fatal diseases

45
Q

Explain the genome of ebola

A

NP = nuclear protein
VP = viral protein
GP = glycoprotein
L = polymerase gene

cleavage by host furin

46
Q

What are natural hosts for ebola and why is it only found in particular countries?

A

Climate has to be right
Pteropodidae fruit bats are the natural hosts of Ebola
These bats are only present in the countries infected
bat has a very advanced immune systems - they have the virus but it doesn’t matter

47
Q

What 3 reactions does reverse transcriptase catalyse

A

RNA dependent DNA synthesis
RNA degradation
DNA dependent DNA synthesis

48
Q

What does integration of the HIV genome into the host genome require

A

Integrase

49
Q

Explain Integration and retrotransposition of viral DNA into the host genome

A
  1. integrase cuts viral DNA
  2. Attack of viral DNA on target DNA
  3. Gap filling by DNA repair
    - Either side of integrated viral DNA there is short direct repeats of the target DNA sequence
50
Q

Explain Retroviral-like retrotransposons, common in eukaryotic genomes

A

LTRs at each end (long terminal repeats)

51
Q

Explain nonretroviral retrotransposons in eukaryotic genomes

A

Poly A at 3’ end of RNA transcript; 5’ end is often truncated

a LINE: long interspersed nuclear element (~7000Bp)

no tRNA binding site

52
Q

What % of our genome are repeat sequences?

A

50%

53
Q

Types of transposons

A

LINEs, SINEs, Retroviral-like element, DNA-only transposon ‘fossils’

54
Q

Explain DNA-only transposons, common in eukaryotic genomes

A

Short inverted repeats at each end

Element moves as DNA cut-and-paste mechanism

55
Q

Features of transposons

A

inverted repeats required (min 20 bp)
transposase recognises 
the repeats
transposase 
brings the 
ends together
the 3´OH groups can attack the target chromosome

56
Q

The HIV genome

A

9700 nt’s long
5’
LTR
Gag – encodes capsid proteins
Pol – encodes reverse transcriptase and integrase
Env – encodes envelope proteins
LTR
3’

57
Q

Explain the processing of the HIV genome

A

primary transcript converted into polyprotein
for Pol gene, further poteolytic processing of the polyprotein

58
Q

Explain the pol gene

A

a gene encoding a poly-protein

  • protease: proteolytic processing of the polyprotein
  • integrase: retro-transposition
  • reverse transcriptase: RNA intermediate
  • ribonuclease H: degrade RNA
59
Q

what is the gag gene of HIV required for

A

required to form virus like particles with transcripts

60
Q

LTR features

A

repetitive sequences, several 100 bases in length

tRNA binding sites in LTR help reverse transcription

LTR recognised by integrase for retro-transposition

61
Q

HIV regulatory protein

A

Gag (capsid), Pol (polymerase) and Env (envelope)
Vif, Vpr, Vpu are regulatory proteins with various functions
Rev regulates nuclear export of the RNA
Nef interferes with protein trafficking
Tat regulates transcription

62
Q

HIV life cycle

A

see poster

63
Q

Explain early HIV synthesis

A

Splicing of RNA - Rev, Tat and Nef are translated first

happens inside nucleus then transported out into the cytosol

64
Q

Explain late HIV synthesis

A

Mature RNA must not be spliced

Rev enters the nucleus
Rev binds to the RRE (rev response element)
Rev protects RNA from splicing

This ensures export of unspliced RNA (from nucleus to cytosol)

Now all viral proteins have been synthesised and there is also unspliced RNA (all of which will be packaged into the virus

65
Q

Structure of the GAG protein/gene

A

N-term - MA (pps) - CA(NTD) - CA (CTD) -(pps) SP1 (pps) - NC - (pps) SP2 (pps) - p6 - C-term

66
Q

3D structure of assembled gag and EM structure

A

RW

67
Q

Explain inhibitors that affect the hexamer-pentamer transition of Gag (HIV)

A

Small molecules that bind to the viral CA protein can be potent inhibitors of HIV infection

Capsid-targeting drugs are predicted to exhibit high barriers to viral resistance, and ongoing work in this area is contributing to an understanding of the molecular biology of HIV uncoating and maturation

68
Q

Name a caspid inhibitor that shows promise for clinical development

A

GS-CA1 (discovered in 2017)

69
Q

Explain HIV cell entry

A

HIV Env protein

receptor: CD4
secondary receptor for efficient attachment (CCR5)
1st phase of AIDS
secondary receptor for efficient attachment (CXCR4)
2nd phase of AIDS

70
Q

Examples of viruses that affect immune cells

A

HIV, EBV, Hep B

71
Q

Why do so many viruses choose to invade immune cells

A

blood / immune cells are generally good vessels to travel the body
cells of the immune system end up in lymphoid organs – more cells to infect here

72
Q

define nucleocapsid

A

a capsid 
that encloses the nucleic acid

73
Q

Icosahedral Capsid features

A

10-400nm
advantage - can make the capsid from many copies of few proteins
construction principle - 20 triangular faces
Each triangle is made up from (at least) thee proteins
The simplest virus capsid is made up from 60 proteins

74
Q

What is the T number (in terms of Icosahedral viruses)

A

Triangulation number
Larger viruses contain more than three proteins per triangle
Multiplier is known as the T number
Known: T = 1,3,4,,7,9,16,25

75
Q

Explain capsid formation (T=3) and an example of a virus that undergoes this

A

RW (TBSV)

76
Q

Jelly-roll motif

A

RW

77
Q

Bacterial viruses/bacteriopage conastruction

A

head: icosahedral capsid
tail: helical
typically dsDNA genome

78
Q

Example of plant virus and its construction

A

helical capsid, Ø 15-18 nm, 
length 300 nm
single protein subunit
associated with ssRNA+

79
Q

Explain the structure of viruses that infect bacteria vs plants vs animals

A

Bacteria - usually head + tail, sometimes enveloped, rarely helical or icosahedral

Plants - usually helical, sometimes icosahedral, sometimes enveloped (less), not head + tail

Animals - usually icosahedral or enveloped, not helical/head + tail

80
Q

What is Vaccinia vs cowpox vs Variola

A

Vaccinia: The vaccine virus

Cowpox (CPXV)

Variola: the disease virus (smallpox) - specific to humans

81
Q

Features of Vaccinia (VACV), Cowpox (CPXV), Variola (VARV)

A
  • enveloped, size 140-260 nm diameter
  • linear dsDNA genome, covalently closed, 130-375 kB
  • mRNA & protein synthesis in cytosol
    E early I immediate L late
  • replication & maturation in cytosol
  • “wrapping” in trans-Golgi membranes
  • Poxviridae, virus factories
82
Q

Vaccinia envelope packaging

A

RW

83
Q

Explain the two forms of smallpox

A

intracellular mature virus (IMV, fusion) and extracellular enveloped virus (EEV, endocytosis)

Both forms are infectious (EEV is more virulent).

84
Q

Explain poxvirus encoding approx 200 proteins

A

Early phase:
essential viral proteins transcribed by viral RNA polymerase
uncoating and release of of viral genome into cytoplasm
Immediate phase:
2 hrs post infection triggers genomic DNA replication

Late Phase:
structural proteins
viral assembly
Virus release
direct release: IMV
passage through Golgi: EEV

85
Q

Smallpox life cycle

A

RW

86
Q

Pox: Viral factories

A

cytoplasmic or perinuclear
recruit specific structures
cell organelles, e.g. mitochondria, Golgi
organise membrane structures: perinuclear replication complexes
exclude host proteins
interfere with signalling
enable viral replication

87
Q

When was smallpox declared eradicated

A

1980

88
Q

Types of vaccines

A

Live attenuated
Inactivated (killed antigen)
Subunit (purified antigen)
Toxoid (inactivated toxins)

89
Q

Adenovirus – gene therapy and vaccination

A

DNA virus
Popular vector for gene therapy in monogenic diseases
Example: CF, cystic fibrosis
Recombinant Adenovirus is being used as COVID19 vaccine
(AZ vaccine, Sputnik 5)

90
Q

Explain RNA vaccines

A

delivered in fatty acids LNPs (lipid nanoparticle)
for COVIS - candidates generated in weeks rather than months

91
Q

Icosahedral virus example

A

Papovaviridae (italics) - HPV

92
Q

HPV life cycle

A

RW

93
Q

Human papillomavirus HPV features

A

more than 70 (120) strains
icosahedral capsid
55 nm diameter
dsDNA
8 kB circular genome
encodes:
L1 + L2 capsid proteins, E1 + E2 replication, E4 + E5 assembly / release, E6 + E7 oncogenic proteins

94
Q

Explain how HPV influences cell cycle regulation

A

E6 dependent ubiquitination and degradation of p53
E7 deregulates the tumor suppressor pRb

95
Q

Explain how HPV infections aren’t usually persisrtant, but what happens when they are

A
  • 70 % healed after one year, 90 % healed after two years
  • HPV6 and HPV11 cause 90% of all genital warts

persistent infection - risk of cancer
HPV16 and HPV18 cause 70% of all cervical cancers

96
Q

Viral life cycles

A

Lytic EBV
- acute
- linear dsDNA

Latent EBV
- genome inactive
- circular dsDNA form

Chronic: Hepatitis B
- long term
- low levels of virus production

Transforming: Pappilloma
altering cell growth

97
Q

Explain a vaccine against cancer

A

HPV Vaccination prevents against cancer

HPV6/11 causes 90% of all genital warts
- cervix, vulva, vagina, anus, penis
- transmitted through sexual contact

HPV16/18 cause 70% of all cervical cancers
Cervarix protects against HPV16/18
Gardasil protects against HPV16/18 & HPV6/11
Nobel Prize 2008 to Harald zur Hausen

98
Q

What protein protects against host immunity in herpes virus and when is it made

A

Tegument proteins, made in immediate early stage

BIOL3017 - Molecular and structural basis for disease (6 decks)

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