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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

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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

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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 are the consequences of many HCV genotypes?

A

-often no cross-neutralisation
-several vaccines needed

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11
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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12
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 high levels of PI4KA (otherwise no replication)

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13
Q

how does HCV enter the cell?

A

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

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14
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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15
Q

How are membrane bending and alterations induced by HCV?

A

NS3-NS5a relevant
NS4B induces formation of membrane alterations

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16
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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17
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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18
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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19
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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20
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)

21
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

22
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

23
Q

what is the problem with available HCV treatment options?

A

too expensive

24
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

25
Q

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

A

bovine viral diarrhea virus (BVDV)

26
Q

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

A

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

27
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)

28
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

29
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)

30
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

31
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

32
Q

what is essential for production of infectious pestiviral progeny?

A

uncleaved NS2-3

33
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

34
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

35
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

36
Q

What are the models of RNA recombination?

A

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

37
Q

which RNA recombinations take place in pestivirus?

A

-insertion
-duplication
-deletion
-integration of cellular sequences

38
Q

Different viruses modify different intracellular mebranes. Name examples

A

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

39
Q

how is the genome organized of flavivirus?

A

-5’cap
-uncleaved NS5 with capping activity
-NS1: essential for RNA replication, induces leakiness of blood vessels

40
Q

what are the characteristics of dengue virus?

A

-mosquito transmitted
-4 serotypes

41
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

42
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

43
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

44
Q

what are the effects of zika virus infection?

A

only mild symptoms but leads to microcephaly when fetuses are infected

45
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)

46
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

47
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’ enbd

48
Q

Name the viruses belonging to the flaviviridae family

A

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

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