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Chemotherapy intercalation > Lecture 2 HIV Hep C > Flashcards

Lecture 2 HIV Hep C Flashcards

1
Q

What is the definition of a virus?

A

A non-cellular micro-organism that can only replicate within cells

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2
Q

What does it mean by ‘obligate intracellular parasites’?

A

Has to be inside the cell to replicate

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3
Q

Describe the structure of a virus

A 
protein coat (capsid) surrounding a nucleic acid genome 
Can be enveloped = surrounded by lipid membrane, may have glycoproteins on the membrane to interact with the host cells 
non enveloped = only a protein and genome 
[see slide for image]
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4
Q

Is the genome made from DNA or RNA?

A

Depends on virus, can be either

Also can be single stranded, duplex, circular or linear

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5
Q

Described the simplified virus life cycle

A

Cell entry → RNA/protein synthesis → genome replication → protein synthesis → assembly of infectious virus particles → release from the cell (cycles back to cell entry)

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6
Q

What does a virus need from the host cells?

A

Raw materials for synthesis of biomolecules (proteins) e.g. nucelotides, amino acids
Machinery for synthesis of biomolecules e.g. protein synthesis requires hosts ribosomes as the virus does not have any
Enveloped viruses need membranes
Transport around the cell
Life! - viruses cannot replicate in a dead cell

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7
Q

What are the ideal characteristics of antiviral drugs?

A

Cell membrane is permeable
No activity against cellular targets - needs specificity
Inhibition of virus encoded protein/virus specific function/process - specificity
Targets critical stage of virus life cycle
No resistance

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8
Q

What is HIV?

A

Human immunodeficiency virus
Causes acquired immunodeficiency syndrome (AIDS)
RNA retrovirus

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9
Q

Which cells does HIV infect?

A

CD4+ cells e.g. T-lymphocytes
Macrophages
Dendritic cells

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10
Q

How is HIV defined by WHO?

A

Progressive qualitative and quantitative decline in CD4+ lymphocytes

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11
Q

How many types of HIV is there and which is more harmful?

A

HIV 1 = human aids

HIV 2 = also causes immunosuppression but less harmful, mainly in africa

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12
Q

Which area of the world has the highest death rate in 2016 from HIV/AIDS

A

Sub saharan africa - also the biggest decline in deaths

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13
Q

Which area of the world has the highest newly infected rate in 2016 from HIV/AIDS

A

Sub Saharan africa - though it is reducing

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14
Q

Explain the trend in the number of people accessing antiretroviral therapy

A

Increasing in number

20 million treated out of 35 million suffering

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15
Q

What are the 3 stages of the course of the HIV infection?

A

1) primary phase illness
2) Asymptomatic stage
3) AIDS

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16
Q

What is viraemia?

A

the presence of viruses in the blood

High = high infection

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17
Q

Explain what happens in the primary illness phase

A

Influenza like illness - virons distribute throughout the body
Sharp rise in viraemia
Increase in HIV specific cytotoxic level = effective at reducing viraemia
Antibodies produced
[See slide for image]

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18
Q

What is the relevance of the set point?

A

The lower the set point, the greater the chance of survival of the patient

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19
Q

Explain what happens in the asymptomatic phase

A

~10+ years
Immune response is controlling the viraemia level well - cytotoxic level stable and high, viraemia stable and low
Antibody level stable
[See slide for image]

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20
Q

Explain what happens in the AIDS phase

A

Viraemia increases rapidly and CD4 level decreases as well as cytotoxic cells and antibodies
Death around 2 years later
[See slide for image]

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21
Q

What is the structure of a HIV particle?

A

Enveloped virus
2 copies of RNA
[see slide for image]

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22
Q

What enzyme is responsible for transcribing the viral RNA into double-stranded DNA? What is this process known as?

A

Reverse transcription

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23
Q

Explain the HIV life cycle

A

HIV virus binds and fuses with host cells membrane → RNA is converted into DNA via reverse transcriptase → DNA enters the nucleus via intergrase enzyme → DNA is transcribed and translated to form viron → maturation of viron occurs via protease enzyme = now infective

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24
Q

What enzyme is inhibited by NRTI/NNRTI’s?

A

reverse transcriptase

25
Q

What 3 classes of drugs are licensed to treat HIV?

A

Nucleoside analogue reverse transcriptase inhibitors (NRTIs)
Non nucleoside analogue reverse transcriptase inhibitors (NNRTIs)
Protease inhibitors (PI)

26
Q

What is HAART?

A

Highly active retroviral therapy
Triple therapy
Usually 2 NRTI’s and NNRTI or PI

27
Q

How long is HAART treatment given for?

A

lifetime therapy

reduces viraemia in 8 weeks

28
Q

Name 4 examples of NNRTIs

A

Nevirapine
Etravirine
Delavirdine
Efavirenz

29
Q

How do NNRTIs work?

A

Inhibits reverse transcriptase by binding to the allosteric site
Does not stop thymidine binding unlike NRTIs

30
Q

Name 3 examples of NRTIs

A

Azidothymidine (AZT)
2’,3’-dideoxyinosine (ddl) - analogue of adenosine
Dideoxycytidine (ddC) - analogue of deoxycytidine

31
Q

How do NRTIs work?

A

analogue of thymidine - 100 fold more affinity for reverse transcriptase than cellular polymerases (so not that specific) = chain termination

32
Q

Can you treat with NNRTIs and NRTIs at the same time?

A

Yes as they both target reverse transcriptase but in different ways
Reduces chance of resistance

33
Q

Explain the process of HIV maturation

A

Budding of the cell occurs which shows electron dense material on the outside of the cell
The virus is released and Gag and Gag-Pol is cleaved by the protease enzyme into individual proteins = electron dense material now in the middle
[see slide for image]

34
Q

Name 2 examples of protease inhibitors

A

Saquinavir

Nelfinavir

35
Q

How does the protease inhibitor class work?

A

Competes with the peptide the protease enzyme normally cleves
Protease inhibitors are membrane permeable to be able to target the virus
Protease is unique to virus = specific

36
Q

What are 3 pros to HAART therapy?

A

Manipulate treatment to avoid resistance
Treatment interruptions - stopping the medication for a period of time when the patients develops resistance so that the resistant virus have to compete with all the other viruses and the number reduces
Highly effective at reducing viral load and disease progression

37
Q

What are 5 cons to HAART therapy?

A 
Cost
Compliance - effects lifestyle
Side effects
Drug-drug interactions
Post therapy reversion - removing the patient off the drug = viral load increases
38
Q

How many people does WHO estimate to be infected with Hep C?

A

73 million

39
Q

Which is more prevalent, HIV or Hep C?

A

Hep C - 6 million new infections per year

40
Q

What are the consequences of Hep C virus?

A

Chronic liver disease i.e. Fibrosis, cirrhosis and hepatocellular carcinoma

41
Q

What is the most common genome group of Hep C?

A

1

Very variable and can mutate easily

42
Q

What is the most problematic genome group of Hep C in the UK?

A

3

43
Q

What percentage of people with Hep C go on to have the chronic infection

A

85%

44
Q

What does the NS3 gene code for?

NS = non functional

A

protease and helicases

Therefore cleaving and separating strands of DNA

45
Q

What does the NS5B gene code for?

NS = non functional

A

RNA dependent RNA polymerase - makes RNA copies of the RNA genome
Differs from HIV polymerase as makes RNA not DNA

46
Q

What does the NS5A gene code for?

NS = non functional

A

Not sure as no enzymatic activity but still used as a drug target

47
Q

Explain the Hep C replication cycle

A

Virus binds and enters cell via endocytosis → uncoating → translation and polyprotein processing/RNA replication → virus budding into intracellular vessicles → transported outside of the cell to fuse to the membrane and release
NOTE: no maturation is required, the virus is already infective

48
Q

Give 2 examples of 1st generation NS3 proteases

A

Telaprevir

Boceprevir

49
Q

Give an example of a 2nd generation NS3 proteases

A

Simeprevir

50
Q

What are the characteristics of 1st generation NS3 proteases?

A

Potent
Prone to resistance
Specific to genotype 1

51
Q

What are the characteristics of 2nd generation NS3 proteases?

A

Potent
Effective against first generation resistance
Effective against some other genotypes but not GT3

52
Q

Name 2 examples of 1st generation NS5A inhibitors

A

Daclatasvir

Ledipasvir

53
Q

How do NS5A inhibitors work?

A 
predicted to target specifically domain I protein of NS5A which has roles in:
Virus RNA replication (with domain 2)
Virus assembly (with domain 3)
Binding to viral RNA (all domains)
Binding multiple cellular factors
54
Q

How potent are NS5A inhibitors?

A

HIGHLY! very low dose of drug needed

55
Q

Name an example of 2nd generation NS5A inhibitor

A

velpatasvir

Pan genotypic

56
Q

Name an example of a NS5B inhibitor and how it works

A

Sofosbuvir

RNA polymerase production is inhibited

57
Q

What is the guideline treatment for Hep C genotypes 1-12 via NICE recommendations?

A

Sofosbuvir (NS5B) + Velapatasvir (NS5A)

58
Q

What is the guideline treatment for Hep C genotypes 1-12 via FDA recommendations?

A

Sofosbuvir (NS5B) + Velapatasvir (NS5A) + Voxilaprevir (NS3)

59
Q

What is around the total cost of Hep C treatment for 12 weeks?

A

£40000

Chemotherapy intercalation (14 decks)

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