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I&I Chaz > Viruses > Flashcards

Viruses Flashcards

1
Q

What are virus exclusive polymerases?

A

RNA dependent RNA polymerase

RNA dependent DNA polymerase- reverse transcriptase

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2
Q

How do viruses get envelopes ?

A

Viruses that can exit an infected cell without destroying it
Viruses that exit via budding can leave the membrane intact
Enveloped viruses synthesis several classes of proteins that stud the membrane so it can continue infection

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3
Q

Name the seven viral groups

A 
1- ds DNA viruses eg. HSV
2- ss DNA viruses eg. Parvovirus
3- ds RNA virus eg. Reovirus
4- (+) sense RNA virus eg HCV
5- (-) sense RNA virus- influenza 
6- RNA reverse transcribing virus- HIV
7- RNA reverse transcribing virus- HBV
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4
Q

Describe the formation of virus particle envelopes

A

Mostly viral particles use the cellular membranes as site of assembly, could be the nuclear envelope, Golgi membrane or the plasma membrane
Matrix proteins- internal proteins that link the capsid to the envelope- usually glycosylated
Glycoproteins- external- anchored in the membrane by a transmembrane domain (sometimes 2)
-transport channel- contain several transmembrane domain forming a protein lined channel

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5
Q

Describe virus penetration

A

Fusion from within
pH dependent
Takes advantage of receptor recycling- escapes the endosome usually via acidification by viral protein pumps
Fusion from without
pH independent
Binding with a receptor that transports it across the membrane

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6
Q

Describe genome packaging

A

Eg. The helical plant virus TMV
The packaging signal (psi signal) in the viral genome allows the virus to differentiate between the genomic nuclei acids and cellular background
The origin of assembly sequence (OAS) in the nucleic acid binds to a disc protein that form rings encasing the nucleic acid
The front face condenses twice as fast as the back so the OAS is usually found 1/3 of the way through the nucleic acid

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7
Q

Describe the early events of virus invasion

A

Random collision with cell- initial electrostatic attraction because of opposite charge
Only binds if the cell has an appropriate receptor- enveloped viruses use their surface glycoproteins- determines tropism as the trimeric glycoproteins have affinities
Non-enveloped viruses use capsid proteins
Virus hijacks cell surface molecule to aid it’s entry
Some cell receptors have more than virus and some viruses use for than one receptor

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8
Q

What is the significance of heptad repeats?

A

Used by viruses eg. HIV when docking at the plasma membrane
Found on the virus envelope
Facilitate fusion from within and escape from the endosome

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9
Q

How do viruses get to their targeted compartments in the cell?

A

Uses localisation signals when travelling via the cytoskeleton
Eg. HIV uses the same localisation motif that histones uses to get to the nucleus- capsid is disassembled on binding with the nuclear pore and the DNA is imported in

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10
Q

How does tropism affect virus production?

A

Virus may be able to bind but not enter, enter but not replicate, replicate but not mature
Eg. Human influenza requires a specific protease found only in airway epithelial cells

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11
Q

Describe the genome replication of class 4 viruses?

A

Single stranded +sense RNA

Transcription of protein can occur directly from the virion RNA after replication

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12
Q

Describe the genome replication of class 5 viruses

A

Single stranded -strand RNA that required replication before it can be transcribed- ha to make dsRNA intermediate

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13
Q

Describe the genome replication of class 3 viruses

A

Double strand RNA

Replication has to occur before transcription is known to occur in a partially dissembled virion

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14
Q

Describe the genome replication of class 6 viruses

A

Reverse transcribing RNA
Single strand +sense RNA with a DNA intermediate
Replication generates a DNA copy of the RNA which integrates into the host genome

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15
Q

Describe the genome replication of class 7 viruses

A

Reverse transcribing DNA viruses
DsDNA with an RNA intermediate
The cDNA copy of the virus is generated during exit not entry

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16
Q

Describe the genome replication of class 1 viruses

A

DsDNA
Virus has proteins- immediate early that switch proteins on
Early proteins are non-structural proteins that orchestrate the host
Late proteins- structural proteins
Happens in nucleus

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17
Q

Describe the genome replication of class 2 viruses

A

Single stranded DNA

SsDNA intermediate is packaged into virion and replication usually occurs before any transcription of protein

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18
Q

Describe vital entry strategies

A

Picornaviruses have many viruses that all utilise the sane receptors
Eg. 91 strains of the Rhinovirus all use ICAM1 so does coxsackie A
Ebola can use many different receptors as one virus eg. DC-SIGN, TREM, APC, asialoglycoprotein, TLR, NPC1- this means that it has many tropisms and an infect many types of cells
Hepatitis C binds to many receptors in sequence which process tropism for liver cells SR-B1➡️ CD81➡️ CLDN1➡️ occludin➡️ entry

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19
Q

What is the significance of eIF-4G in VEHCS?

A

Component of the eLF-4F cap binding complex which acts as a bridge between the eLF-4E cap structure and the 40S subunit if the ribosome
Cleavage eIF-4G by VP2A inactivated cap-dependent translation with eLF-4A
Then the internal ribosome entry site (IRES) of the poliovirus can directly recruit 40S TK the viral RNA and initiate cap-independent translation

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20
Q

What other methods are involved in VEHCS and eIF-4G?

A

DNA and -RNA viruses dephosphorylate eIF-4E do it does not bind to eIF-4G
+RNA viruses dephosphorylate eIF-4Ebp so eIF-4E cannot bind to eIF-4E
Rotaviruses make a eIF-4G binding protein, nsP3, which makes the cap complex eject the host RNA by displacing the poly-A bp Pab1b allowing the virus RNA to bind nsP3 and populate the initiation complex
The influenza virus inserts viral transcript into the open reading frame of host RNA transcripts

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21
Q

Describe the genome structure of +ssRNA viruses

A

Linear
Cassette organisation of structural proteins and non structural proteins
Usually 5’ methyl caps and polyA tails (except picornavirus has Vpg cap and flavivirus doesn’t have polyA tail)
Usually 5’ and 3’ UTRs )except coronavirus)

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22
Q

Describe the genome structure of -ve sense RNA viruses

A

Can be simple or complex
Simple- rhabdoviruses contains many starts, stops and polyAs, paramyxovirus contains pause signal to effect ribosome shuttling and arenaviruses ambisense
Multipartite viruses have segmented genomes that are packaged into multiple particles eg orthomyxovirus
Filovirus eg Ebola initiations of some proteins can overlap with others

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23
Q

Describe herpesviruses

A

Subfamilies of alpha, beta and gamma
Alpha- herpes simplex virus 1 and 2 (HSV1,2) and varicella-zoster virus (VZV)
Beta- cytomegalovirus (CMV), human herpes virus 6 and 7 (HHV6,7)
Gamma- Epstein Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV)
Enveloped with a icosadeltahedral capsid
Linear dsDNA- replicate in the nucleus
Glycoproteins embedded in lipid envelope for receptor mediated entry
Tegument between envelope and capsid that induces viral gene expression and VEHCS and virus assembly

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24
Q

Describe the human herpes viruses

A

Alpha- HSV1,2 (mucoepithelial cells) and VZV (B cell, epithelial cells) variable host range, short replication cycle, rapid spread in culture and efficient destruction of infected cells
Beta- CMV (epithelial cells, monocytes, lymphocytes), HHV6,7 (T lymphocytes) restricted host range, long replication cycle, slow spread
Gamma- EBV (B cells, epithelial cells), KSHV (B cells, endothelial) restricted host range, usually specific for lymphocytes, latent infection in lymphocytes, relocation in culture is infrequent
They can be latent (no virus protein expression, immunologically silent, episomal DNA replicated with host DNA) or lytic (virus DNA replication, new progeny viruses made, virus protein expressed, highly immunogenic)

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25
Q

Describe herpesvirus binding and entry into the host

A

Conserved glycoproteins
Glycoproteins B, H, L, M, N
Receptor mediated endocytosis or direct fusion with the plasma membrane

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26
Q

Describe a herpes virus life cycle

A
  1. Viral DNA circularisation
  2. Expression of immediate early genes to transactivate viral DNA replication and inhibits host promoters
  3. Expression of early genes- viral replication
  4. Expression of late genes- structural genes
  5. Production of viral capsid, tegument, glycoproteins
  6. Production of viral progeny- PM makes the virus envelope
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27
Q

Describe herpesvirus DNA replication

A

They encode their own proteins for viral DNA replication- ssDNA binding protein, origin binding protein, helicase-primase complex, DNA polymerase, polymerase prices diving factor
1. Input DNA is circularised upon entry to the cell
2. Origin binding protein binds to specific sequences within the origin of replication
3. The origin binding proteins begin to unwind the DNA
4. The unwinding DNA forms a replication bubble
5. The origin binding protein begins to recruit ssDNA binding proteins
6. The origin binding proteins and ssDNA binding proteins to the replication forks
DNA is nicked during replication to form a rolling circle

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28
Q

Describe the clinical manifestations of herpes simplex infections

A

Infection via mucosal surfaces
Replication in oral or genital mucosa
Invasions via sensory endings
Neurovirulence- invade and replicate in the CNS, severe neurological devastation
Latency- HSV1 in the trigeminal ganglion
HSV2 in the sacral ganglia
Severity directly related to type of immunosuppressive therapy used after a transplant
More exaggerated, frequent and anti-viral resistant in HIV/AIDS

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29
Q

Describe the clinical manifestation of cytomegalovirus

A

Usually clinically silent in healthy people
Congenital CMV- in utero infection of multiple systems
Can cause graft-verses-host disease in immunocompromised transplant patients
Cause pneumonitis, eosophagitis, gastritis, enterocolitis, hepatitis in transplant and HIV/AIDS

30
Q

Describe the clinical manifestation of EBV infection

A

95% of population infected by adulthood
Usually asymptomatic
Delayed infection can result in glandular fever
B lymphotropic- remains latent in memory B cells (CD21 and HLA2 or gp350 and gp42)
Person to person transmission of epithelial cells
Can result in malignancies Burkitt and Hodgkin lymphoma, nasopharyngeal and gastric carcinoma, extranodal NK/T cell lymphoma, NK leukaemia

31
Q

How could you characterise a latent infection?

A

Viral gene products that promote productive replication are not made
Cells harbouring latent genome are poorly recognised by the immune system
Viral genome persists intact so that productive infection can be initiated to ensure spread to new hosts

32
Q

Describe the stages of HSV infection of the host

A
  1. Productive infection of epithelial cells at the primary site of infection
  2. Secondary site of infection and site of latent infection: the sensory neuron
  3. Site of recurrent infection- productive replication in epithelial cells
33
Q

What are mechanisms of EBV- induced tumourigenesis

A

Co-factors like immunosuppression, and additional cellular genetic changes
Rate incidence of persistent virus infection
EBV expresses different patterns of virus gene expression which complement genetic changes within the cell to initiate and maintain tumour phenotype
Eg. EBNA2- TF interacts with notch pathway- induces proliferation
EBNA1- TF activates viral and cellular genes
EBNA3A and 3C- TF chromatin remodelling and changes in cellular gene expression
LMP1- activates cellular genes

34
Q

How could you characterise a latent infection?

A

Viral gene products that promote productive replication are not made
Cells harbouring latent genome are poorly recognised by the immune system
Viral genome persists intact so that productive infection can be initiated to ensure spread to new hosts

35
Q

Describe the stages of HSV infection of the host

A
  1. Productive infection of epithelial cells at the primary site of infection
  2. Secondary site of infection and site of latent infection: the sensory neuron
  3. Site of recurrent infection- productive replication in epithelial cells
36
Q

What are mechanisms of EBV- induced tumourigenesis

A

Co-factors like immunosuppression, and additional cellular genetic changes
Rate incidence of persistent virus infection
EBV expresses different patterns of virus gene expression which complement genetic changes within the cell to initiate and maintain tumour phenotype
Eg. EBNA2- TF interacts with notch pathway- induces proliferation
EBNA1- TF activates viral and cellular genes
EBNA3A and 3C- TF chromatin remodelling and changes in cellular gene expression
LMP1- activates cellular genes

37
Q

Describe DNA virus replication

A

Requires expression of at least one viral protein- delay after infection
Host cell provides other proteins
Induces host factors and cell cycle regulators
Virus encoded immediate early and early protein- polymerase or induction of host to express the polymerase
Ori recognition
Prime DNA synthesis- RNA- Okazaki fragments, DNA-hairpin structures, protein covalent lay bonded to the 5’ end
Elongation
Termination

38
Q

What is the difference between large and small DNA viruses?

A

Small- polyomavirus, papilloma virus, parvovirus encode proteins that orchestrate the host
Have to deregulate growth control of cells
Large- herpesvirus, adenoviruses, pox viruses, encode most of their own replication proteins, replicate in slow or non-dividing cells

39
Q

Describe human papilloma viruses

A

Non-enveloped
Two different capsid proteins
Three regions of genome: early- non-structural, late- structural and non-coding
Dependent on host cell for replication and transcription- E2 loads E1 onto ori, which further loads more E1 into s double hexamer which can recruit cellular replication factors
Early gene 6 and 7 stimulate cell growth
Infect epithelial surfaces eg. Skin, lining of the above it’s tract and oropharynx- cause benign warts

40
Q

Deprive HPV life cycle in epithelial cells

A

Infection into a wound
Replicates outside host DNA- induces cell proliferation
As the cells move through the layers they multiply and assemble to be released as the cells are shed

41
Q

How does HPV orchestrate the host cell?

A

E7 binds and degrades RB which leads to premature S phase progression
E6 induces p53 degradation to pre vent up apoptosis of infected cells

42
Q

Describe the clinical burden of hepatitis C virus

A

Over 300,000 seats per annum
170 million infections worldwide
Have a variable genome
75% of infections become chronic and can lead to hepatocellular carcinoma

43
Q

Describe HCV lifecycle

A

Membrane assembled- hydrophobic- assemblosome
Has an IRES with the start codon inside it
1. Binding
2. Receptor-mediated endocytosis
3. Virion-endosome membrane fusion
4. Uncoating
5. Translation and polyprotein processing
6. Membrane associated RNA replication
7. Virion morphogenesis in intracellular vesicle
8. Virion transport and glycoproteins maturation
9. Vesicle fusion at the plasma membrane- virion release

44
Q

Describe HCV anti-antiviral mechanisms

A

Virus protease targets TLR3 and MAVS for degradation to stop dsRNA detection and immune responses

45
Q

What defines HVC tropism?

A 
CD81- HCV E2
SR-BI- HCV E2
CLDN1-
OCLN
Only hepatocytes have all the necessary receptors
46
Q

What is the function of interferon?

A

Produced by the infected cell in response to PAMPs
Autocrine and paracrine signalling of interferon to prevent virus spread
Can be administered to patients as an antiviral

47
Q

Describe HCV therapies

A 
Interferon- 50% response
Interferon/Ribaviron- combo more effective than interferon- resolution can be 90%
Sofobuvir
Rapid virological responders- RVR
Sustained virological response- SVR
Response with relapse- RR
Non-responders- NR
Resolve depends I number if epitope a targeted, degree of viral suppression, frequency of CD8+ subsets, mutations in the virus
48
Q

What do retroviruses have in common with RNA viruses?

A

Small genomes
Multifunctional proteins are common
Higher mutation rate
Many members modulate host cell translation using virally encoded factors
Viral proteases act in concert with host proteases to define protein maturation

49
Q

Summarise the life cycle of retroviruses

A 
Attachment
Penetration- most pH independent but can also use pH dependent fusion
Uncoating
Replication in nucleus
Assembly
Release-
50
Q

Briefly describe the genesis of procurator DNA from HIV vRNA

A

The tRNA lysine is a host RNA whose 3’ end acts as a primer for cDNA synthesis
The RNA is eventually replaced- the remnants form a polypurine tract primer
RNAse H destroys the RNA in a RNA-DNA duplex
Replication can be RdDp or DdDp

51
Q

How does the DNA integrate?

A

Linear 2 long terminal repeat vDNA
(Can also produce 1 LTR circle or 2 LTR circle- indicator if viral replication)
Integrase- nuclease and ligase action
Random insertion into chromosome

52
Q

Describe HIV transcription

A

Can utilise host slicing machinery to generate a complex set of transcripts in all 3 reading frames
Induces frameshifts- ribosome ‘stutters’ at a string of 6 Us and reads 5 instead

53
Q

Describe HIV maturation

A

When the p55 protein to cleaved by protease into p24 and p17

It goes from infectious to non-infectious

54
Q

What is the significance of CCRF5?

A

32 nucleotide deletion in CCR5 leads to loss of protein
Homozygous are resistant to HIV
Also resistant to yersinia pestis- high incidence of mutations in European countries heavily effected by the plague

55
Q

What are HERVs?

A

Human endogenous retroviruses
‘Best adapted’ virus incorporate themselves into the germline by getting into the gametes and become self in the second generation
8-9% of the genome consists of HERVs
TI-2 recognition of foreign antigens and Genesis of IgM is mediated by HERVs expressed in response to B cell engagement

56
Q

Describe HBV

A

Entry
Translocation to nucleus and completion of second stand synthesis to give long lived close covalent circle cccDNA form of virus
Transcription of cccDNA to generate many mRNA including the pre-genomic RNA
Translation of proteins- reverse transcriptase
RT of pgRNA gives ssDNA copy
Second strand synthesis
Export and envelopment of capsid via ER to give progeny virus

57
Q

Describe HIV transcription

A

Can utilise host slicing machinery to generate a complex set of transcripts in all 3 reading frames
Induces frameshifts- ribosome ‘stutters’ at a string of 6 Us and reads 5 instead

58
Q

Describe HIV maturation

A

When the p55 protein to cleaved by protease into p24 and p17

It goes from infectious to non-infectious

59
Q

What is the significance of CCRF5?

A

32 nucleotide deletion in CCR5 leads to loss of protein
Homozygous are resistant to HIV
Also resistant to yersinia pestis- high incidence of mutations in European countries heavily effected by the plague

60
Q

What are HERVs?

A

Human endogenous retroviruses
‘Best adapted’ virus incorporate themselves into the germline by getting into the gametes and become self in the second generation
8-9% of the genome consists of HERVs
TI-2 recognition of foreign antigens and Genesis of IgM is mediated by HERVs expressed in response to B cell engagement

61
Q

Describe HBV

A

Entry
Translocation to nucleus and completion of second stand synthesis to give long lived close covalent circle cccDNA form of virus
Transcription of cccDNA to generate many mRNA including the pre-genomic RNA
Translation of proteins- reverse transcriptase
RT of pgRNA gives ssDNA copy
Second strand synthesis
Export and envelopment of capsid via ER to give progeny virus

62
Q

Compare influenza and measles particle and genome

A

Influenza- Negative strand RNA virus- 7-8 RNA segments
Particles covered in neuraminidase and haemagglutinins
Measles- negative strand RNA virus- non-segmented
Particles covered in haemagglutinin and fusion proteins

63
Q

Briefly describe the replication cycle of measles and influenza

A

Influenza- nuclear genome replication

Measles- cytoplasmic genome replication

64
Q

Describe the attachment and entry of measles and influenza

A

Measles- attaches to proteins in the surface
-CD150 on immune cells
-Nectin-4 on epithelial cells
Enters by fusing at the PM and/or by endocytosis, pH independent, H-receptors triggers fusion proteins
Influenza- sialic acid fusion receptor
Entry through endosomes, pH dependent, low pH triggers HA cleavage and M2 ion channel activation

65
Q

Compare the transcription of influenza and measles

A

Influenza- segments transcribed by viral polymerases (PB1/PB2/PA) and gene transcription is determined by polymerase binding efficiencies, mRNA caps stolen form host mRNAs in the nucleus
Measles- gene expression is regulated using a transcriptional gradient
Genes closer to the promoter are are transcribed with greater frequency, makes its own mRNA caps as it replicates in the cytoplasm

66
Q

Why is influenza more difficult to irradiate than measles?

A

Segmented genome allows for reassortment
Higher mutation rate- RNA virus polymerases make a lot of mistakes
Common receptor leads to easy infection of many cell types
Measles cannot evolve away from its highly immunogenic epitope in its CD150 binding domain

67
Q

How does interferon kill viruses?

A
  1. Upregulation of 2,5-oligo A synthetase- activates endogenous RNAse L which cleaves RNA
  2. 68kD RNA-activated protein kinase- when IFN activates p68 which phosphorylates eIF2alpha inactivating it- essential for IRES mediated translated
  3. Flu specific- activation of Mx histone protein which binds to flu genomic RNA and reduces the rate of transcription
68
Q

What are the advantages and disadvantages of viral drug discovery?

A

Highly specific- safe for patient but limited utility for diverse viruses
Definided specificity- but resistance mutation occurs rapidly
Relatively rapid to develop
Relatively costly to manufacture

69
Q

Name some inhibitors of viral DNA polymerase

A

Acyclovir
Gangcyclovir
Nucleotide analogues- viral polymerase tried to incorporate them- chain termination
Inhibitors of herpes simplex and other dsDNA viruses

70
Q

Name some inhibitors of viral RNA polymerase

A

Ribavirin

Inhibitor of several RNA viruses- not very effective

71
Q

Name some inhibitors of reverse transcriptase

A

Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine
Non-nucleoside reverse transcriptase inhibitors (NNRTs)- space filling molecules

72
Q

What is HAART and what is the problem with it?

A

Highly Active AntiRetroviral Therapy
Uses multiple drugs with different targets to prevent resistance stopping therapy
No patient has been cured
Majority of patients show undetectable viral load of transcriptionally inactive HIV

I&I Chaz (5 decks)

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