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Stage 4 Content > HIV > Flashcards

HIV Flashcards

1
Q

How does Glycoprotein120 work?

A

It bind to CD4 and causes a conformation change in GP120, which leads to binding of CCR5 or CXCR4 to reveal GP41

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2
Q

How does GP41 work?

A

It punches a hole in the cell surface of normal cell which causes a fusion with the Host cell and HIV-1 cell so the HIV-1 cell can release the content into the normal cells

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3
Q

What are the 6 stages of viral replication cycle related to HIV?

A

Stage 1 - attachment to host cells - HIV uses GP120 to bind to CD4 and that causes conformational change on gp120 so then can bind to either CCR5 or CXCR4 which reveals GP41.

Stage 2 - Penetration of host cell & Stage 3 - uncoating of the virus - HIV is non-enveloped virus so GP41 can punch a hole in the host cell and spills its content into it.

Stage 4 - Replication of genetic material - this is two process in HIV via TRANSLATION and TRANSCRIPTION (catalysed by reverse transcriptase). Transactivating protein transcriptase ‘TAT’ acts with cellular proteins in HIV to increase viral transcription

Stage 5&6 - maturation and budding - HIV develops an envelop via a complex process through infusing its glycoproteins in host’s membrane.

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4
Q

What’s the difference between NucltoTIDES and NucloSIDES?

A

NucleoTIDES:

  • Has 3 phosphate,
  • Pentose sugar
  • base (A, T/U, C, G)

NucleoSIDES:
- Pentose sugar
- Base
Nucleosides are phosphorylated by kinases to become Nucleotides.

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5
Q

What can you change on a Nucleotide?

A

The pentose sugar.

  • RNA has 2 OH on the 2’ and 3’.
  • Removal or substitution of both the 2’ and 3’ OH produces ‘obligatory chain terminators’ of the polymerisation process.
  • main bases used are C, T & G
  • A not usually used because it is readily metabolised and interferes with adenosine metabolism.
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6
Q

What is the structure of Reverse Transcriptase?

A

It is a

  • Hetereodimeric enzyme
  • has 2 polypeptide
  • has a finger, palm and thumb structure
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7
Q

What is the function of Reverse Transcriptase?

A
  • Polymerase

- Endonuclease (RNAse -H)

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8
Q

What is Reverse transcriptase complex?

A

It contains:
Reverse transcriptase
LEDGF-p75
Integrase

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9
Q

What is the transcription process of viral RNA to double-stranded DNA?

A
  1. Reverse transcriptase polymerise Viral RNA to make a complementary viral DNA.
  2. RT then uses endonuclease to cut out the viral RNA
  3. RT then polymerises the single stranded DNA into double stranded DNA and a ‘pre-integration complex’ is formed.
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10
Q

What are the two classes of Reverse transcriptase inhibitors?

A
  • NRTI - nucleoside reverse transcriptase inhibitor

- NNRTI - non-nucleoside reverse transcriptase

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11
Q

What is the MOA of NRTI

A
  • NRTI must be phosphorylated to be active because they are analogues of endogenous 2’-deoxy-nucleosides.
  • phosphorylation occurs inside the cell by nucleophile attack on the phosphate.
  • NRTI are hydrophilic and have limited membrane permeability so they are transported into the cell via solute carrier transporters
  • NRTI act on the active site and lack a 3’-hydroxyl group, so they prevent chain elongation.
  • they are ‘obligatory chain terminators’
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12
Q

Examples of NRTI

A
  • Truvada (TDF & Emtricatabine)
  • Descovy (TAF &Emtricatabine)
  • Kivexa (Abacavair & Lamivudine)
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13
Q

Are NRTI toxic to mitochondria?

A

YES

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14
Q

What is the MOA of NNRTI

A
  • All NNRTI act on the hydrophobic allosteric site on the palm.
  • The pockets are hydrophobic so NNRTI needs a high logP (between 2-3)
  • Binding of NNRTI to RT results in conformational change in RT
  • This causes the movement of aspartic acid residues in the active site which inhibits the enzyme.
  • NNRTI also disrupts the movement of the thumb which is important for transcription.
  • So this causes a reduced thumb mobility, so preventing/slowing translocation of the primer/template.
  • Binding of NNRTI can influence RNAse-H activity of the RT enzyme
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15
Q

Examples of NNRTI

A

1st Gen: EfaVIRenz, NeVIRapine

2nd Gen: RilpiVIRine, DoraVIRine

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16
Q

What’s the difference between 1st Gen and 2 Gen NNRTI

A

1st Gen - composed of aromatic ring which are locked so resistance to it is easy

2nd Gen - Aromatic rings can move & switch past each other, so binding is maintain in allosteric pocket.

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17
Q

What is the structure of Integrase?

A

Has 3 domains:

  • N-terminal domain (NTD)
  • Catalytic-core domain (CCD)
  • C-terminal domain (CTD)

-operates as a tetramer.

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18
Q

What is the function of the 3 domains of Intrgrase?

A
  • NTD - has Zn ion which helps stabilises the NTD and is required for enzyme activity.
  • CCD - The active site has 2 Mg 2+ ions which is important for 3’-processing and strand transfer. 2 Mg+ ions act as lewis acid and reacts with Lewis base (phosphate). Also has 3 charged amino acid.
  • CTD - binds DNA non-specifically
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19
Q

Can integrase affect the rate of reaction of RT

A

Yes because they have a relationship.

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20
Q

What does the pre-integrase complex consist of?

A
  • Integrase

- Viral DNA

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21
Q

What is the importance of LEDGF-p75

A
  • it stabilises Integrase

- disruption means the viral particle is incomplete and cannot integrate.

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22
Q

What is the function of Integrase

A
  • 3’ processing

- strand transfer

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23
Q

What is the process of 3’ processing

A
  • It occurs in the cytoplasm

- after the RT makes double stranded DNA, Integrase cuts off 2 ends of the DNA to make ‘sticky ends’

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24
Q

What is the process of strand transfer

A
  • it occurs in the nucleus - leading to permanent infection.

- After the ‘sticky ends’ have been made, Integrase transfers the Viral double stranded DNA in-between the host cell DNA

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25
Q

How does LEDGF-p75 work?

A
  • it binds to the CCD-CCD interface on one dimer and simultaneously binds to the NTD of another dimer.
  • this stabilises the integrase tetramer
26
Q

Examples of Integrase inhibitors

A

1st Gen: RalteGRAVIR, Elvitegravir

2nd Gen: DoluteGRAVIR, BiceteGRAVIR

27
Q

What’s the difference between 1st Gen and 2 Gen Integrase inhibitor

A

2nd Gen:

  • are in a co-planar arrangement so are locked and efficient in chelating to Mg2+ ions.
  • the ring is hydrophobic so can lock to hydrophobic region of the binding site
  • it has a low cross resistance/good barrier to resistance, good safety barrier, few drug interactions and fewer SE.
28
Q

What’s the similarity between 1st Gen and 2 Gen Integrase inhibitor

A
  • they both cannot be used in medication with aluminium based antacid OR containing Ca 2+ions or other metal chelators
  • both gen are metal chelators
  • they both chelate Mg 2+ ions via Lewis base-lewis acid interaction.
29
Q

MOA of Integrase inhibitor

A
  • Blocks strand transfer from occurring
  • metal chelation of Mg2+ ion via Lewis acid-lewis base interaction
  • the inhibitors have different residence times in the active site of the enzyme
30
Q

What is the role of HIV protease

A
  • generates new viral particles
  • involved in the cleavage of non-functional long polypeptide into functional proteins e.g Matrix proteins, Capsid proteins.
31
Q

What are the two types of proteases?

A
  • peptidases - cleave single amino acid from the end of the peptide chain
  • proteinases - cleave peptide bond within a substrate and is the focus
32
Q

What is the structure of Protease

A

has 3 domains:
-dimerisation domain - crucial for dimer formation

  • core domain - useful for catalytic stability and contains catalytic triad (aspartate, threonine and glycine)
  • flap domain - enclose the active site and provides ligand-binding interactions
33
Q

How does HIV protease work, using aspartic acid?

A
  • aspartate essential for both catalytic and structural
  • Asp 25 and Asp 25’ + water induce general acid/base amide hydrolysis
  • Protease looks for unique sequence ‘Phe-Pro’ in the Gag-pol infusion protein and cleaves the amide bond between ‘Phe-Pro’ by using water.
34
Q

What is the MOA of protease inhibitors

A
  • mimic intermediate formed by protease but it has no OH, or 1 OH, or OH on different bond.
  • this means there is no leaving group so the protease inhibitor is stuck to the active site
35
Q

Does protease inhibitors require boosting?

A

YES.

they use CYP450 inhibitors to boost half-life.

36
Q

Examples of protease inhibitors

A

AtazaNAVIR, DaruNAVIR

37
Q

Pharmacokinetic boosters for PI examples

A

Cobistat

Ritonavir

38
Q

Characteristics of Cobistat

A
  • has no anti-viral activity
  • causes increased serum creatinine conc.
  • does not cause lipodystrophy or induction of insulin resistance
  • can enhance levels of: CCB, B-BLOCKERS, STATIN & ERECTILE DYSFUNCTION DRUGS
39
Q

Characteristics of Ritonavir

A
  • long term use associated with GI problems

- increases conc of LDL, cholesterol and triglyceride

40
Q

What does the graph show?

A
  • Viral load – red line
  • At beginning of infection – rapid increase. As immune response kicks in it goes down. Higher viral load more likely to transmit it sexually.
  • CD4 count – blue line
  • Virus attacks CD4 quick. As immune response activate it recovers to a somewhat level. Deteriorates slowly till immune system becomes compromised, then you start to see opportunistic viruses and cancers due to weak immune system.
41
Q

What are the 2 diagnostic test for HIV

A
  • 4th generation assay - ELISA - sensitive after 4 weeks

- point of care testing (POCT) -high accuracy after 6 weeks

42
Q

What are the markers of HIV

A
  • CD4 count - no. of CD4 cells in 1 microlitre of blood. CD4% more accurate presentation
  • Viral load - no. of HIV RNA in 1ml of blood.
43
Q

What are the 5 scenarios to start treatment

A
  1. Primary infection - offer treatment early in detection
  2. Chronic infection - start when patient is ready to start ARV
  3. Presentation with AIDS or major infection - start within 2 weeks of antimicrobials of patient presenting with AIDS-defining illness
  4. Prevention of onward transmission - should be discussed alongside wider safe sex conversation
  5. ARV prophylaxis:
    - post-exposure prophylaxis (PEP) - 28 day treatment initiated within 72 hrs after exposure

-pre-exposure prophylaxis (PrEP) - taken daily or PRN if you can predict contact

44
Q

What are the pros and cons of early treatment?

A

Pro:

  • increased immunological recovery
  • decreased transmission
  • decreased disease progression & morbidity
  • reassurance to patient

Con:

  • poor preparation leads to low adherence and drug resistance
  • cost
  • long-term side effects
45
Q

What are the drug-food interaction with ARV

A
  • food reduces GI side effects such as ritonavir

- increases absorption of lipid soluble drug

46
Q

What are drug-drug interaction with ARV

A

Absorption:

  • changes to gastric pH - atazanivir and rilpivirine are contra-indicated with PPI
  • chelation - integrase inhibitors with polyvalent ions
  • transport proteins - shunts drugs in and out of cells

Metabolism:
-inhibiton/induction of enzymes: CYP450
-St John’s Wort induces CYP450 so ACOID with protease inhibitors
-potenital interaction:
Diabetes, hyperlipidaemia, neuro-psychotic illness, hypertension, OTC, statins, erectile dysfunction.

47
Q

What are the goals of treatment

A
  • improve QOL
  • Immunological - restore CD4 count

Virological - VL undetectable within 4-6 months

Epedimology - prevent transmission

48
Q

Pros and Cons of protease inhibitor

A

Pro:
-high efficacy

Con:
-drug interactions 
-cost expensive 
-side effects:
peripheral neuropathy, headache, lipodystrophy, abdominal pain 
-LOW BARRIER TO RESISTANCE
49
Q

Pros and Cons of Integrase inhibitors

A

Pro:

  • HIGH BARRIER TO RESISTANCE
  • few side-effects
  • few drug interactions
  • rapid virological response

Con:
-cost - expensive

50
Q

Pros and Cons of NNRTIs

A

Pro:

  • high efficacy
  • relatively few side-effects

Con:
Efavirenz - contra-indicated in previous psychotic illness
-Rilvipirine - can only be used if VL <100,000
-Drug interactions
-LOW BARRIER TO RESISTANCE
-Atazanavir & Rilpirivine - contra-indicated with PPI.

51
Q

What is treatment failure associated with?

A
  • Poor adherence

- Resistance

52
Q

What is the pharmacokinetic of Abacavir

A
  • cautioned in CVD risk
  • 8% allergic to it
  • Avoid in patient w/ HLA-B*5701 gene positive
53
Q

How does NRTI cause a range of toxicity

A

Because NRTI inhibit mitochondrial polymerase and leads to elevated plasma lactate.

54
Q

How doses resistance occurs with NNRTI

A
  • NNRTI does not target the active site therefore HIV can change the amino acid in the allosteric binding site meaning NNRTI cannot bind anymore BUT the catalytic active site can still work
55
Q

More about Nevirapine?

A
  • has high CNS penetration

- different pharmacodynamic effect dependent on ethnicity and sex

56
Q

More about Efavirenz

A
  • Induces CYP enzymes
  • Extensive hepatic metabolism
  • Effect on CNS can be pronounced
57
Q

More about Rilpiravine

A
  • Lower CNS incidence
  • Taken with food
  • Metabolised by CYP3A so caution when taking inducers/inhibitors
58
Q

More about Doravarine

A
  • metabolised by CYP3A
  • no dose adjustment required for patients w/ hepatic impairment
  • pharmacokinetic is not affected by age, gender or ethnicity
59
Q

Comparison of TDF and TAF

A

TDF

  • acitvated in the plasma
  • has negative effects on renal function and bone mineral density
  • renal accumulation due to high efficient uptake from plasma w/ decreased efflux into urine

TAF

  • activated intracellularly
  • can use lower dose because it is metabolised intracellularly
  • lower plasma conc. w/ fewer side-effects
60
Q

What is the regimen for patients who are resistant to 1st line/women who want to be pregnant/ patients w/ psychiatric illness

A

2x NRTIs + a boosted protease inhibitor

Boosted protease inhibitor:

  • Atazanvir + Ritonavir or cobistat
  • Darunavir + Ritonavir or cobistat

Stage 4 Content (18 decks)

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