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MBBS IV - Supplementary Courses > Molecular Genetics - HPV and HBV (II) > Flashcards

Molecular Genetics - HPV and HBV (II) Flashcards

1
Q

Structure of HPV

A

Non-enveloped dsDNA virus with supercoiled genome

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2
Q

List 2 high risk and 2 low risk HPV genotypes.

Associated diseases?

A

High risk: 16,18
Oncogenic, HSIL, Cervical cancer

Low risk: 6,11
Anogenital warts, LSIL

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3
Q

2 oncogenes commonly detected in cervical cancer.
Activity in low risk and high risk HPV types?
Function of these oncogenes?

A

HPV oncogene E6 and E7

high transforming activity in high risk HPV

Interact with growth-regulating targets in host cells.
E6&raquo_space; p53, E7&raquo_space; pRb

> > Maintain malignant phenotype of cervical carcinoma cells

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4
Q

Primary prevention against cervical cancer?

A
  • HPV vaccination

- Avoid risk factors

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5
Q

Secondary prevention against cervical cancer?

A
  • Cervical cytology/ HPV test screening

- Detect pre-invasive lesion of uterine cervix (HSIL)

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6
Q

3 reasons HPV infection persists?

A
  • Evades normal immune mechanisms
  • Do not produce humoral immune response
  • Diagnostic serology test not widely available
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7
Q

3 main types of HPV DNA test

A

1) HPV pooled DNA test
2) HPV genotyping
3) HPV pooled test + High risk HPV 16/18 genotyping

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8
Q

3 purposes of HPV genotyping test

A
  • Epidemiology
  • Assess clinical behavior of subtypes
  • Design targeted therapy and vaccine
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9
Q

Most important factors that validate HPV molecular tests

A

1) Quality control and clinical validation in diagnostic settings
2) Adequate data to correlate between cut-off point and detection of cervical cancer and precursor lesion

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10
Q

In situ hybridization.

used for which type of HPV test?

A

Early HPV detection

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11
Q

PCR sequencing

- used for which type of HPV test?

A

HPV detection
HPV genotyping
(+/- Detect multiple HPV)

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12
Q

Describe HPV DNA chips function

A

PCR products of L1 and E6, E7 gene sequences are hybridized to arrayed probes on the chip&raquo_space; DNA sample with target genes bind to probes

HPV genotypes identified by fluorescence scanner

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13
Q

List techniques for HPV testing *****

A
  • HPV DNA chip: Genotype by gene products
  • Qualitative multiplex assay and RT-PCR
    HPV detection
    HPV high risk genotype 16,18
    Identify multiple HPV infection
  • RNA transcription detection
    Persistent HPV infection
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14
Q

Qualitative multiplex assay

- used for which type of HPV test?

A

HPV detection
HPV high risk genotype 16,18
Identify multiple HPV infection

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15
Q

RT-PCR

- used for which type of HPV test?

A

HPV detection
HPV high risk genotype 16,18
Identify multiple HPV infection

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16
Q

Which targets are tested in extended HPV genotyping (check)

A

E6,E7 DNA regions

Screen for all 14 high-risk HPV types

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17
Q

Best test for persistent HPV infection?

A

RNA test:
RNA transcript detection

more specific for detection of persistent infection and detection of HSIL than DNA test

18
Q

Invasive cervical cancer and high grade lesion is suspected based on clinical exam
Order 2 tests for confirmation

A

Co-testing:

Pap-smear + HPV DNA testing

19
Q

Define ASC-US and associated risks

A

Atypical squamous cells of undetermined significance

  • Cytological abnormalities, higher risk of LSIL or HSIL
20
Q

Triage of ASCUS

- Next step after detection of ASCUS through cytology testing

A

Cytology and HPV co-testing

1) Repeat cytology again at 6 months and 12 months
a) Positive for ASCUS or LSIL/ HSIL in both tests = colposcopy
b) Both Normal results = repeat cytology again in 3 years

2) HPV testing
a) High risk HPV positive = Colposcopy
b) High risk HPV negative = Repeat cytology or co-testing at 3 years

21
Q

Purpose of ASCUS triage?

A

Reduce patient anxiety
Decrease cost of repeat smears
Earlier Dx of HSIL

22
Q

One other cancer associated with HPV

Testing method?

A

HPV 16&raquo_space; Oropharyngeal squamous cell carcinoma

Increase incidence in men with age

IHC for p16 as surrogate marker from tissue specimen

23
Q

3 un-recommended use of HPV tests

A

Low risk test

Test under 25

Reflexive HPV test after Pap smear of HSIL

24
Q

HPV +ve and HPV -ve cervical cancer

  • Associated with which risk factors
  • Which has better prognosis
A

HPV +ve = sexual behavior
HPV -ve= smoking and tobacco

HPV +ve has better prognosis

25
Q

Method for test of cure after excision of high grade cervical carcinoma in situ?

A

High risk HPV test + cytology to monitor recurrence

12 months and 24 months after excision

Both negative = return to normal screening interval

26
Q

Method for testing for HPV infection in uterine cervix SCC and Adenocarcinomas.

A

IHC for p16 surrogate marker + HPV DNA testing

27
Q

Genome structure and method of genetic replication in HBV

A

4 overlapping reading frames to make protein
Partially dsDNA virus

P - polymerase/ reverse transcriptase
S - HBsAg
C - HBcAg and HBeAg
X - HBx

Replicates via reverse transcription

28
Q

Form of HBV DNA that can reactivate inside hepatocytes and indicate treatment?

A

cccDNA

Covalently closed circular DNA
Remains inside hepatocyte nucleus even after treatment

29
Q

Describe the time course of anti-HBc and anti-HBs antibody development after infection.

A

1-2 months after: Generate Anti-HBc IgG and Anti-HBc IgM
IgM level drops after few months
IgG level persists

3 months after: Generate Anti-HBs
Level slightly decreases over decades

30
Q

First phase of HBV infection:

  • HBV DNA level? HBsAg and HBeAg?
  • Liver enzyme level?
  • Host reaction?
A

HbeAg- positive infection (Immune tolerance)

  • High HBV DNA, HBsAg present, HBeAg present
  • Normal AST, ALT (small spike up to 1 month)
  • No host reaction
31
Q

Second phase of HBV infection

  • HBV DNA level? HBsAg and HBeAg?
  • Liver enzyme level?
  • Host reaction?
A

HBeAg- positive hepatitis (Immune clearance) —> HBeAg negative hepatitis

  • HBV DNA fluctuate, HBsAg present, HBeAg present +/- Anti-HBe
  • AST/ ALT fluctuate
  • Active hepatitis > symptomatic
  • Cytotoxic T cell kill infected hepatocytes
32
Q

Third phase of HBV infection

  • HBV DNA level? HBsAg and HBeAg?
  • Liver enzyme level?
  • Host reaction?
A

HbeAg- negative infection (inactive carrier)

  • HBV DNA low HBsAg present, Anti-HBe present
  • Low AST/ALT
  • Frequent cirrhosis/ HCC
33
Q

Fourth phase of HBV infection

  • HBV DNA level? HBsAg and HBeAg?
  • Liver enzyme level?
  • Host reaction?
A

HBsAg-negative

  • Cannot detect HBV DNA, Anti-HBs and Anti-HBe present
  • Normal liver enzyme
  • HCC/ Cirrhosis possible
34
Q

Role of HBV DNA testing (4)

A
  • Indicate infectivity/ disease activity
  • Find HBV in HBsAg-negative cases
  • Indicate risk of progression to HCC/ Cirrhosis
  • Predict antiviral treatment outcome and drug-resistance
35
Q

Process of HBV DNA testing?

  • Sample?
  • Steps?
A

Whole blood (EDTA or clotted blood)

1) Centrifuge for plasma/ serum
2) Lysis/ extraction of HBV DNA
3) Signal/ target amplification (e.g. PCR)
4) Fluorometric or colorimetric measurement

36
Q

Advantage of new HBV assays over old assays?

A 
Higher sensitivity (can detect at very low conc.)
Much shorter time
37
Q

Over entire course of HBV infection, when to do HBV DNA test?

A

1) Test newly infected patient - indicate disease activity, plan treatment
2) During antiviral therapy - predict drug response or resistance
3) After stopping antivirals - check persistent infection

38
Q

MoA of antivirals for HBV infection.

Name 4

A

Nucleoside analogues = NRTI

Chain terminator of DNA synthesis and inhibits reverse transcription

Nucleoside analogues:
Lamivudine
Entecavir

Nucleotide analogues
Tenofovir: Tenofovir alafenamide or Tenofovir disoproxil fumurate (for WT and Lamivudine resistant HBV)

Interferon-a therapy +/- steroid for immune rebound enhancement

39
Q

1 gene sequence that confers resistance to antivirals in HBV. What type of mutation?

A

Reverse transcriptase gene mutation confers resistance
» Polymerase/ Reverse transcriptase mutation

YMDD gene mutation

> > YVDD&raquo_space; Methionine to valine SNP

40
Q

Which Antiviral for HBV has highest resistance rate?

A

Lamivudine

41
Q

List 3 HBV markers

A

cccDNA
HBsAg
HBeAg

42
Q

How to assess amount of cccDNA transcription in HBV infection?

A

Quantitative HBsAg assay

Reflects transcription activity of cccDNA

MBBS IV - Supplementary Courses (54 decks)

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