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Vilo > Flaviviridae > Flashcards

Flaviviridae Flashcards

1
Q

What does the genome of flaviviradae look like?

A

-positive RNA
-single stranded
-IRES
-no poly A
-1 ORF –> Polyprotein
-lipid envelope

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2
Q

how can HCV be detected?

A

-ELISA
-Westernblot
-RT-PCR

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3
Q

What are the risk factors for HCV infection?

A

-iv Drugs
-sexual
-transfusion

–>communication by blood

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4
Q

What are the clinical features of HCV (incubation, immunity, therapy)?

A

incubation: 2-26 weeks
immunity: no permanent protection –> reinfection
therapy: PEG-interferon, directly acting drug, no vaccine

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5
Q

what is the genomic variability of HCV like?

A

high

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6
Q

describe the course of HCV infection

A

HCV infectiion leads to either:
virus elimination or persistent infection

persistent infection can develop further into chronic hepatitis –> liver cirrhosis –> carcinoma

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7
Q

why is it difficult to study HCV?

A

only valid animal model is chimpanzee –> many data only from cell culture

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8
Q

which parts of the immune system react first and which last?

A

innate immune system (hours)
cellular immune response e.g t cells (days)
antibodies (weeks)

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9
Q

What are persistance strategies of HCV?

A

1.suppression of the innate immune system
-NS3/4A complex cleaves TRIF and Cardif –> no signaling through TLR3, TLR4, no recognition of ctyoplasmic dsRNA
2.very high antigenic variability
-8 genotypes
-high number of viruses formed per patient with 1-10 exchanges per genome copy –> preexisting resistance are spread, even if most viruses are killed by drug, then still enough survive especially the resistant ones and can spread again

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10
Q

What does NS3 in HCV need for full protease activity? What is it essential for?

A

cofactor NS4A needed –> essential for viral replication

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11
Q

what are the consequences of many HCV genotypes?

A

-often no cross-neutralisation
-several vaccines needed

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12
Q

what is the basis for all drugs in clinical testing against HCV?

A

HCV replicon system;
-reduction of genome size to minimal set of genes required for RNA replication
-integration of selectable marker
-selection pressure: cells without HCV replication die
-surviving cells form colony
-replicating HCV RNA can be isolated and sequenced
-insertion of viral structural genes in replicon allows entire replication cycle in cell culture

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13
Q

what is the basis for HCV RNA replication in cultered cells?

A

adaptive mutations: mutations in NS5A and NS5B to allow for high level RNA replication in presence of very high levels of PI4KA (otherwise no replication)

In wt cells there is a low level of Pi4KA and NS5A and NS5B lead to elevated PI4KA levels (needed for recruitment of other molecules to the membrane in order for replication taking place at membrane). In cell culture (hepatoma cells) there is already a very high level of PI4KA and even more induction by the virus is too much (delicate balance). Thats why mutations are needed

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14
Q

how does HCV enter the cell?

A

via receptor mediated endocytosis: CD81, LDL, SR-BI, CLDN1, OCDN

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15
Q

Explain the role membranes play in HCV

A

All proteins are directly or indirectly linked (amphipathic helices) to membrane (membranous web, ER, mitchondrial membranes)–> membrane topology is critical for RNA replication and processing by cellular ER localized proteases

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16
Q

How are membrane bending and alterations induced by HCV?

A

NS3-NS5a relevant
NS4B induces formation of membrane alterations

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17
Q

Describe the membranous web

A

vesicles are protrusions of the ER membrane
single and double membrane vesicles
vesicles are frequently connected to the ER via neck-like structures

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18
Q

what role do lipid droplets play in HCV?

A

-lipid droplets are loaded with viral and cellular proteins
-viral proteins at LD membrane mediate interaction between lD and ER membrane
-unloading of viral proteins from LD to generate virions

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19
Q

What role plays miRNA122?

A

-miRNA122 is liver specific –> liver tropoism of HCV
-HCV replication dpends on cellular miRNA122: direct interaction of miRNA122 with two target sites in 5’UTR –> binding increases stability and translation of HCV RNA

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20
Q

what would be the effect of silencing miRNA122 as a HCV therapy?

A

-reduce HCV RNA abundance
-reducing host steatosis (effect on lipid metabolism)
–> miRNA122 attractive target for therapy

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21
Q

Why can most patients not be cured by pegINF and Ribavirin?

A

-genotype of virus is critical
-genetics of the host (different reponses in different ethnicities)

22
Q

Name course of infections with examples

A

1.acute Infection: influenza
2.persistent:
2a.chronic: HCV
2b.latent: Herpes simplex virus
2c.slow infection: HIV

23
Q

Name HCV therapy targets

A

-inhibitors of viral serine protease NS3/4A
-inhibitors of RNA pol (NS5B)
-NS5A antagonist
-silecing of miRNA122
-virus assembly inhibitors

24
Q

what is the problem with available HCV treatment options?

A

too expensive

25
Q

which animal models can be used for HCV? What is the problem?

A

northern tree shrews: can be infected, mild hepatitis, develop chronic infections

–>BUT are hard to handle, yet no other animal models exist

26
Q

which virus is a model for a lifelong verius persistence without detectable adaptive immune response?

A

bovine viral diarrhea virus (BVDV)

27
Q

why do some cattles have no adaptive immune response to BVDV?

A

intrauterine infection:
infection of mother during precnancy –> infection of fetus –> fetus’ immune system recognizes virus as self-antigen –> acquired pathogen specific immunotolerance

28
Q

how can BVDV suppress the innate immune system?

A

N-terminal protease binds interferon-regulatory factor 3 –> no interferons synthesis in infected cells

enveloped protein ribonuclease secreted: binds dsRNA and blocks IFN induction

no cytopathogenic biotype of the virus (no apoptosis)

RNA replication/protein translation on a low level (NS3 levels)

29
Q

Name 4 strategies for virus persistance of BVDV

A

1.intrauterine infection
2.suppression of the innate immune system
3.suppression of apoptosis
4.high antigenic variability of the surface antigens

30
Q

What is needed in BVDV infection to suppress apoptosis/innate immune system?

A

stringent regulation of NS3 levels required because the amount of NS3 regulates efficiency of replication (RNA synthesis is limited by the free amount of NS3)

31
Q

how can cleavage NS2-3 of BVDV be inhibited?

A

by consumption of cellular cofactor pool (Jiv(DNAJC14)

–> uncleaved NS2-3 is not part of replicase, only free NS3

32
Q

describe the temporal regulation of pestiviral NS2-3 cleavage

A

early phase: efficient RNA replication due to cleavage of NS2-3 via Jiv -

late phase: low level of RNA replication because NS2-3 is not cleaved because Jiv pool depleted

33
Q

What is required for replicase assembly and what for virion assembly in pestivirus?

A

free NS3 (cleavage): replicase assembly

uncleaved NS2-3 required for virion assembly

34
Q

what is essential for production of infectious pestiviral progeny?

A

uncleaved NS2-3

35
Q

what is required for NS2-3 independent virion morphogenesis of pestiviruses? what is it useful for?

A

two gain of function mutations:
1.NS2/E440V
2.NS3/V132A
–>weakening the NS3/NS4A kink interaction because AA132 of NS3 is located at the kink
–>viral particle assembly in the absence of uncleaved NS2-3

36
Q

for what is the NS3/4A surface interaction critical? What happens if the interaction is weakened?

A

RNA replication –> weakening the interaction results in a gain of function morphogenesis –> functional switch: alternative conformations in the NS3/4A complex result in alternative function in the viral replication cycle (but only a slight reduction in NS3/4A surface interaction is tolerated)

37
Q

What role does ubiquitin insertion play in pestivirus?

A

ubiquitin insertion serves as processing signal for cellular ubiquitin–specific proteases for:
-deregulated cleavage of NS2 and NS3
-upregulated RNA replication
-viral cytopathogenicity and disease

38
Q

What are the models of RNA recombination?

A

1.template switching during viral RNA replication
2.breakage and ligation (independent of viral replication)

39
Q

which RNA recombinations take place in pestivirus?

A

-insertion
-duplication
-deletion
-integration of cellular sequences

40
Q

Different viruses modify different intracellular mebranes. Name examples

A

ER: HCV, Polio
ER/Golgi/intermediate: Kunjin virus
lysosomes: Rubella
Mitochondria: Flock house virus

41
Q

what is unique for the genus flavivirus compared to the other genuses of the flaviviridae family?

A

-5’cap, no IRES
-uncleaved NS5 with capping activity
-NS1: essential for RNA replication, induces leakiness of blood vessels

42
Q

what are the characteristics of dengue virus?

A

-mosquito transmitted
-4 serotypes

43
Q

how can dengue virus be transmitted?

A

1.transmission via salvia of mosquito
2.local reproduction, transport into local lymphnodes
3.infection of leukocytes
4.viremia
5.virus uptake
6.virus replication in gut
7.infection of salviary glands, replication and transmission

44
Q

what are the possible consequences of dengue infection?

A

1-symptomless
2-dengue fever
3-secondary infection with heterologues serotype leads to
3a: dengue hemorrhagic fever
3b: dengue shock syndorme

45
Q

what is antibody dependent enhancement of infection

A

-virus uptake/infection mediated via interaction of non-neutralizing antibodies and cellular FC receptors
-viremia and spread throughout body by infected phagocytes

–> may also arise by primary infection or may be transmitted from mother to child or secondary infection

46
Q

what are the effects of zika virus infection?

A

only mild symptoms but leads to microcephaly when fetuses are infected

47
Q

How can West Nile virus be transmitted?

A

Birds are reservoirs (epizootic amplification between birds and mosquito)

mosquitos transmit them to humans and horses (dead end hosts = no reinfection of mosquito)

48
Q

how does flaviviral RNA replication work?

A

RNA genome with 5’cap but no polyA at 3’end
communication between genome ends via base pairing –> cyclisation

no initiation at 3’UTR fragment
replication initiation in trans by binding of RdRp to 5’UTR –> initiation at 3’end

spacer required for flexibility

49
Q

how does replication of dengue virus work?

A

1.cyclisation of the genome via base pairing
2.binding of RdRp to 5’end
3.Transfer of polymerase from 5’ to 3’ end
4.Start of RNA synthesis at 3’ end

50
Q

Name the viruses belonging to the flaviviridae family

A

-Orthoflavivirus
-Hepacivirus (HCV)
-Pegivirus
-Pestivirus (BVDV)

51
Q

How do flavivirus, influenza virus and poliovirus achieve communication between genome ends?

A

-flavivirus: cyclisation (base pairing)
-influenza: genome segments (panhandle/cork screw structure)
-polio: protein bridge

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