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ID Week 2 > ICL 1.7: Hepatitis Viruses II > Flashcards

ICL 1.7: Hepatitis Viruses II Flashcards

1
Q

which hepatitis viruses and transmitted parenteral?

A

Hepatitis B, C, D

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2
Q

what is the family, transmission, vaccine status and chronic potential of HepB?

A

hepadnaviridae

parenteral transmission

there is a vaccine!

it can be chronic and lead to cirrhosis or hepatocellular carcinoma

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3
Q

what is the family, transmission, vaccine status and chronic potential of HepC?

A

flaviviridae family = enveloped (+)ssRNA

parenteral transmission

no vaccine!

it can be chronic and lead to cirrhosis or hepatocellular carcinoma

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4
Q

what is the family, transmission, vaccine status and chronic potential of HepD?

A

virus-like agent, HBV co-infection

parenteral transmission

no vaccine!

can be chronic; it enhances HBV

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5
Q

how can parenteral transmission happen?

A
  1. transfusions
  2. hemodialysis (long term)
  3. needle sticks
  4. sexual and vertical transmission (exchange of bodily fluids)
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6
Q

what is the most common, chronic, blood-borne infection in the US?

A

HepC!

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7
Q

how is HepC different than other flaviviruses?

A

it’s NOT vector born!!

you don’t get it from mosquitos like most of the other flaviviruses we talked about

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8
Q

proteins are important for HepC?

A

HCAg = capsid protein

E and NS1 = viral envelope proteins

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9
Q

what are the clinical features of HepC?

A

HCV infection causes an acute hepatitis

so yes HepC can cause a chronic infection but you’re still going to have an initial acute infection before it establishes a chronic infection

it can lead to a chronic infection in 70% or more of cases**

it can have up to a 20 year latent period….

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10
Q

what are the characteristics of chronic HepC infections?

A

it can lead to a chronic infection in 70% or more of cases** – so a majority of those who get infected with HepC will also get chronic HepC

it can have up to a 20 year latent period….

HepC accounts for 45% of chronic hepatitis (all sources)

it’s the leading cause for liver transplants due to it causing cirrhosis or carcinoma

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11
Q

how does HepC remain chronic? which specific proteins are involved?

A
  1. NS5A protein
  2. NS3/4a protease

HCV proteins interfere with cell defenses and activation of T cell responses

these proteins block our antiviral response to stick around

this means that these proteins are great drug targets!

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12
Q

what does NS5A protein do?

A

HepC viral protein that interacts with cellular translation and blocks interferon signaling

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13
Q

what does NS3/4a protease do?

A

HepC viral protein that blocks the innate immune pathway that recognizes viral infections

this results in no activation of NFkB or IRF3, no interferon, and interferon stimulated genes activated, impaired T-cell activation and recruitment

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14
Q

what is the pathogenesis of HepC?

A

it’s a cytotoxic T cell response!

HLA class I-restricted cytotoxic T cells are probably responsible for most liver damage in HCV

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15
Q

which enzyme level is different in an acute vs. chronic HepC infection?

A

ALT!

in acute HepC infections there’s lots of active tissue damage so ALT levels are high

a chronic infection might not show high ALT levels because the virus isn’t replicating that much and there might not be that much cell damage

this tells you that liver enzymes aren’t the best marker for chronic infections

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16
Q

how do you diagnose HepC?

A
  1. index of suspicion (were you at risk?)
  2. screen for HepC antibodies
  3. RT-PCR to detect viral RNA

liver enzyme assays only monitor liver injury, are insensitive, nonspecific and too late

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17
Q

what would you do if someone was anti-HCV Ab positive vs. negative?

A

screening for anti-HCV antibodies is 92-95% sensitive so it’s a great test to see if someone has HepC

if someone is anti-HCV Ab negative then stop becuase they’re not infected (or it’s too early in the infection and they haven’t produced antibodies)

if someone is positive for anti-HCV antibodies then you should confirm this result by immunoblot and/or RNA assay

also do a medical evaluation for active infection and liver disease

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18
Q

how do you treat HepC?

A

well immune-globulin doesn’t work and vaccines are not available yet…

antibodies aren’t fully protective either as reinfections occur

your innate immune response is what’s important in HCV clearance

older treatments included α-IFN

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19
Q

why was IFN-α used to treat HepC?

A

we naturally produce IFN-α because it has natural antiviral properties!

however, it works best when combined with specific anti-virals that target viral enzymes to inhibit certain steps in the viral lifecycle

for example IFN-α + rabavirin lead to recovery in 5/10 people with genotype 1, and 8/10 for genotypes 2 and 3

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20
Q

what does ribavirin do?

A

it increases error by polymerase, creates lethal number of mutations

used in combination with IFN-α to treat HepC

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21
Q

what are DAAs?

A

DAA = direct acting antiviral agents

used to treat HepC!

DAAs are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase

ex. sofosbuvir
ex. ledipasvir

22
Q

what is sofosbuvir?

A

it’s a DAA = direct acting antiviral agents

it’s used to treat HepC

it’s a nucleotide analogue and NS5B polymerase inhibitor that causes chain termination

23
Q

what is ledipasvir?

A

it’s a DAA = direct acting antiviral agents

it’s used to treat HepC

it’s a NS5A inhibitor

24
Q

what are the issues with DAAs?

A

they’re used to treat HepC by inhibiting NS3/4A protease, the NS5A protein, and the NS5B polymerase

the problem with them are:
1. infection often diagnosed at late stage

  1. high cost of DAAs
  2. re-infection possible
25
Q

what is a Dane particle?

A

the virion form of HepB

it’s just a fancy word for the infectious form of HepB

26
Q

which virus family is HepB and what are the characteristics of the genome?

A

hepadnavirida

enveloped, icosahedral, circular partially dsDNA virus!

there’s a complete (-) strand and one incomplete (+) strand

27
Q

what virion-associated polymerases does HepB have?

A

it’s a DNA virus that’s part of the hepadnaviridae family

so it uses a reverse transcriptase!!

28
Q

which viral proteins are important in HepB?

A
  1. HBcAg (capsid)
  2. HBsAg (envelope)

these proteins are markers for infection!

29
Q

what are sub-viral particles? which hepatitis virus are they associated with?

A

HepB

sub-viral particles are NOT virions

they act as decoys to attract our immune response to them instead of the virus

they are produced in great excess with respcet to the virions and have viral proteins on their surface like HBsAg (HepB envelope protein)

since sub-viral particles are covered in HBsAg, they look like HepC virion and they can soak up some of the antibodies so that the antibodies are getting wasted on these decoy particles

30
Q

where is HepA geographically common?

A
  • south america
  • africa
  • south asia
  • greenland
31
Q

where is HepB geographically common?

A
  • greenland
  • africa
  • south asia
  • northern south america
32
Q

how does HepB replicate?

A
  1. VAP on envelope binds to host cell receptor
  2. endocytosis
  3. uncoating
  4. it’s a DNA virus so genome goes to nucleus to replicate the genome and make mRNA and other proteins

the host polymerase II does transcription of viral DNA into pregnomic RNA which then leaves the nucleus and gets encapsulated

  1. so now we have full length pregenomic RNA in the capsid that was produced from host transcription factors

inside the capsid there are reverse transcriptases that can make DNA from the RNA

so reverse transcription happens!!

  1. (+) RNA is copied into (-)DNA by reverse transcription
  2. reverse transcriptase can also use DNA as a template so it copies the (-)DNA strand to make the (+)DNA strand

the (-)DNA strand is complete while the (+)DNA strand is incomplete so it’s partially dsDNA

  1. budding
33
Q

what are the 3 important HepB antigens?

A
  1. HBsAg = surface antigen, envelope protein
  2. HBcAg = core antigen, capsid protein
  3. HBeAg = e antigen, secreted protein

there are antibodies to all these antigens: anti-HBs, anti-HBc, anti-HBe

34
Q

what is the difference in surface proteins between subparticles and dane particles?

A

HBsAg is a HepB surface antigen that’s an envelope protein

there are 3 forms of HBsAg = LHBsAg, MHBsAg, SHBsAg

only LHBsAg has receptor binding function and can bind to host cells

so dane particles have&raquo_space; L forms of HBsAg while subparticles do not and can’t compete for receptor binding to cells!

there are neutralizing antibodies directed against the “a” determinant that is on all
3 forms of HBsAg

so when neutralizing antibodies bind to LHBsAg, the dane particles can no longer bind to and infect cells and the virus is neutralizied

35
Q

how are HBcAg and HBeAg made?

A

there are 2 in-frame AUG start codons in the core ORF

HBcAg is the translation product of second, or more internal AUG initiation codon so it’s the smaller protein and gets integrated into the virion

HBeAg is the product of the first AUG codon for the pre-C+C ORF so it’s the larger protein and is used during replication but is NOT packaged into the virion

instead it is independently secreted from cells, accumulating in serum as immunologically distinct antigens

so these two proteins are very closely related and have similar AA sequences!

36
Q

what is a good marker of active HepB virus replication?

A

HBeAg

HBeAg passes into the lumen of the ER and is secreted from cells and ends up in the serum

so HBeAg is a great marker of active virus replication because it’s secreted into blood during an active infection and its presence in the blood correlates with viremia

**HBeAg is associated with infectivity

HBeAg is not part of the virion but indicates actively
infected cells

37
Q

how can you tell if it’s an acute or chronic HBV infection based on viral protein levels?

A

ACUTE
in an acute infection, there’s a spike in HBsAg which then rapidly declines – the high HBsAg tells you the HepB virus is present and then when its levels decrease it’s tell you that the virus is being cleared

so since HBsAg is being cleared, there will be super low levels of anti-HBs since it’s being cleared along with the HBsAg

once you start to see anti-HBs levels increase, this tells you that the virus has been cleared but you won’t see if until the virus concentration is low enough that anti-HBs can start to accumulate

also HBeAg stops being produced relatively quickly once active replication stops since it’s an acute infection and anti-HBe levels increase

CHRONIC
in a chronic infection, HBeAg is being produced for a much longer time period since the virus is still replicating

there’s also high, constant levels of HBsAg since the virus is still replicating

38
Q

what does is mean if there is no HBsAg, no anti-HBs, and no anti-HBc?

A

the person isn’t infected but they are susceptible to HepB

39
Q

what does it mean if there’s no HBsAg but there are anti-HBs and anti-HBc present?

A

immune-natural infection

so you were infected by the virus and built antibodies against it

40
Q

what does it mean if there’s no HBsAg or anti-HBc but there is anti-HBs positive?

A

immune-HBV vaccination

you were vaccinated and built up antibodies

but you only have anti-HBs antibodies because they’re the surface proteins that the vaccine would’ve targeted, not the capsid HBc proteins

41
Q

what does it mean if there are HBsAg and anti-HBc present but no anti-HBs present?

A

you’re acutely infected

42
Q

what does it mean if there is no HBsAg or anti-HBs but there is anti-HBc present?

A

interpretation is unclear

you could be resolving an acute infection, we’re not sure

retest in several weeks

43
Q

what are the clinical features of HepB?

A

1) a mild, self-limiting hepatitis followed by full recovery and life-long immunity
2. persistent viral infection with chronic persistent hepatitis
3. acute, fuminant hepatitis
4. primary hepatocellular carcinoma

not all infections turn to chronic infections but acute HBV causes chronic infection in 30-90% of people

44
Q

how do you prevent HepB?

A

there’s a subunit vaccine!!

it’s made of recombinant HBsAg with L,M and S proteins

45
Q

what are the names of the two HepB vaccines we use in the US?

A
  1. Recombivax

2. Engerix-B

46
Q

how do you treat HepB?

A
  1. IFNα
  2. modified nucleoside analogues that inhibit the viral RTase

currently the best treatment plan is Peg-IFNα with lamivudine

47
Q

what type of genome does HepD have?

A

circular (-) ssRNA genome

48
Q

how does HepD replicate?

A

it’s a virus that can only replicate when another virus is around because it doesn’t make its own surface antigen!

so if you have another virus around already making surface antigens, HepD can use them to replicate

most of the time this virus is HepB!!!

HDV contain envelopes of HBsAg (pseudotype) and require coinfection with HBV to produce infectious particles

this would explain how HBV vaccine also protects against HDV infection because HepD is using HepB surface antigens to make itself it will be recognized by the antibodies made against HepB

49
Q

what populations are at risk for HepD?

A

HDV is most prevalent in groups at high risk of hepatitis B

10% of all HBV carriers are co-infected with HDV

50
Q

what are the two major types of HDV infection?

A
  1. simultaneous infection

2. super-infection

51
Q

what is a simultaneous HDV infection?

A

it’s a stimultaneous HDV and HBV infection

this will lead to higher incidence of fulminant hepatitis and severe acute hepatitis

52
Q

what is a HDV super-infection?

A

when you already have HepB and then get infected with HepD on top of it

this increases the risk of chronic HBV infection and cirrhosis

so the big thing with HepD is that it makes HepB worse!!!!

ID Week 2 (20 decks)

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