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Molecular Basis of Disease > HIV > Flashcards

HIV Flashcards

1
Q

What are the tests for HIV?

A

A rapid finger-prick or mouth-swab point-of-care test (POCT)

A blood test requiring lab analysis

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2
Q

Where are HIV tests done?

A 
Sex health/genitourinary medicine clinics
Some GP surgeries
Clinics run by charities
Antenatal clinics
Private clinics
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3
Q

How do 3rd and 4th gen tests for HIV differ?

A

3rd have larger window period (6 weeks compared to 14-20 days) because it looks only for HIV Abs and not p24 antigen

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4
Q

What is a window period?

A

The time between a person becomes infected with HIV until the point when a test can detect HIV infection

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5
Q

Describe the natural history of HIV infection

A

First CD4 cells drop and viral loads peaks (about 6 weeks)

Viral load then drops and CD4 pop rebounds

Then, the CD4 begins to progressively drop and eventually the viral load increases again

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6
Q

Below what CD4 count do contitutional symptoms start?

A

350

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7
Q

At what CD4 count do opportunistic infections affect the host?

A

300-250

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8
Q

What do CD4 counts and viral load tell you?

A

when to intervene in terms of antiretroviral

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9
Q

What is the definition of the HIV viral load measurement?

A

The amount of HIV RNA in peripheral blood

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10
Q

What 3 assays are used to measure viral load?

A

RT-PCR
bDNA (branched DNA test)
NASBA (nucleic acid sequence based amplification)

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11
Q

How does RT-PCR work?

A

Viral RNA is transcribed to DNA with retroviral RT

Millions of copies are amplified using standard PCR

Assay makes even tiny amounts of RNA detectable

Can detect the number of copies being made by primers which make colour or light (real time PCR)

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12
Q

How does bDNA work?

A

Uses nucleic acid hybridization to detect target.

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13
Q

In what way is bDNA better than RT-PCR?

A

Doesn’t rely on PCR and is more quantitative

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14
Q

what does NASBA do?

A

it is a method to amplify RNA seq

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15
Q

How do you find out CD4 cell count

A

Take whole blood

Do an assay based on fluorescence activated cell sorter: Sample is mixed with tagged anti-CD4 Ab which bind to any CD4 cells which the machine counts as a sample flow by the detector

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16
Q

How many times a year are patients’ CD4 cell counts checked?

A

3-4 times (so they know about changes over time)

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17
Q

What does 90-90-90 refer to?

A

90% should know that they have it

Of these 90% should be on treatment

And of this 90% should be virally suppressed

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18
Q

What is the main receptor for HIV and its co receptor?

A

CD4

important co receptor = CCR5

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19
Q

Images of the HIV virus look smooth. Why?

A

Probably there are very few virus gps and they all move to the point where they make contact with the CD4 cell (so the immune system doesnt see it)

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20
Q

What are some adaptations of HIV to not be detected by the immune system?

A

They have few virus gps outside

A glycan shield covers most of it except where it binds the cell (even this can be covered sometimes)

Env (viral envelope forming protein) has has very variable sequence

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21
Q

Describe the HIV replication cycle

A

Attachement and entry —> reverse transcription –> nuclear import –> integration, gene expression, genome replication –> production and release of virus particles

22
Q

How does HIV genome replication occur

A

RT makes a complementary DNA strand to HIV RNA

The RNA strand is degraded

RT makes carries out DNA dependent DNA synthesis for the new DNA strand to make a double stranded DNA

This all occurs in the cytoplasm

The DNA enters in the nucleus where it is integrated in the host genome by integrase

23
Q

How might HIV’s replication cause a problem (for the virus)?

A

The DNA is made in the cytoplasm –> can trigger DNA sensors –> antiviral effect

24
Q

What is the only other time (other than virus infection) when you see DNA in cytoplasm?

A

Mitosis

25
Q

How does HIV prevent its DNA getting detected in the cytoplasm?

A

Capsid

26
Q

How do you get nucleotides into the capsid to make DNA?

A

Each hexomer has a pore in it (core has + charged AAs) which sucks nucleotides in

Acts as a molecular switch to decide whether RT can occur or not

The pore is probably cytoplasmic proteins which the virus recruits

These proteins control pore status and tell the virus where in the cell it is

27
Q

Why is HIV cone shaped?

A

There is an accumulation of pentamers at pointy end

This is probably because that end docks on the nucleus and releases the DNA into the nucleus by opening

28
Q

Where in the genome does HIV integration occur?

A

In transcriptionally active genes adjacent to nuclear pores

29
Q

What happens if you mutate capsid or integrase (with respect to HIV integration)?

A

The integration will happen in a different place in the genome

30
Q

How do HIV particles assemble?

A

Gag proteins are made. Protease first cleaves itself and then cleaves Gag into 5 subunits to make the structure

Round virus particles become cone-shaped

31
Q

What is a marker of T cell activation?

A

CD38

32
Q

What is seen in HIV infections (markers and cells)?

A

Increased CD38

Increased CD8 %

Decreased CD4

33
Q

How do T cells die?

A

Majority of dead CD4 T cells are not infected

Virus tries to infect and fails –> Caspase 1-mediated pyroptosis, a highly inflammatory form of cell death

34
Q

What is the role of the inflammatory process in CD4 T cell death?

A

HIV infection –> pyroptosis –> inflammatory cytokines and cell contents are released –> inflammation –> recruiting healthy CD4 cells –> repeat (chronic cycle)

35
Q

Where was the data about chronic inflammation in HIV taken from?

A

Tonsil explants (from people who might already have been sick and had activated tonsils)

36
Q

Where are most of your T cells?

A

In the gut

37
Q

Why (when it comes to HIV) should we try to sample from different locations in the body?

A

CD4 and innate lymphoid depletion occurs in the gut and does not recover even after treatment

Dysbiosis/ microbial translocation causes more activation

T cells have residency

38
Q

How many zoonoses have lead to HIV?

A

12

39
Q

Which HIV strain causes the HIV pandemic?

A

HIV-1 M

40
Q

Why is HIV 1 M special?

A

Not clear but: 1M is the only one that has a fully functioning pore

41
Q

Why might SIV never lead to AIDS like HIV?

A

Many possible reasons

You don’t see dysbiosis or have chronic immune activation in SIV

42
Q

Why does SIV not have chronic immune activation?

A

Vpx allows it to replicate in non activated cells

Non activated cells can repress HIV (e.g. SAMHD1)

43
Q

Can we cure HIV?

A

We can treat it but if you stop treating then you will get rapid rise in virus again

Visconte cohort: people who stopped taking drugs but the virus was controlled in absence of therapy (unknown why)

The Berlin Patient

44
Q

How do active cells allow HIV to be expressed?

A

NfKb binds to the LTR (promoter for HIV)

Polymerase comes and gets to TAR, which stalls the polymerase

In an activated cell a viral protein called TAT recruits a transcription elongation factor (P-TEFb) which allows RNA polymerase to continue

45
Q

How can you repress proviruses?

A

Downregulate P-TEFb

Sequester NFkB in the cytosol

Epigenetically silence provirus

46
Q

Can we measure the latent reservoir?

A

Very difficult

Peripheral blood is often used but this is not representative of other parts of the body

Has very few cells - most mutated

47
Q

Describe the steps of the kick and kill mechanism

A
  1. ART is used to make sure HIV is not detectable
  2. 2 vaccines train the immune system to recognise cells that will be activated
  3. Vorinostat is used to wake up the sleeping cells
  4. The immune system, boosted by the vaccine, attacks and kills the newly activated cells
48
Q

Is there active replication during effective ART?

A

Yes

Sanctuary sites - replication can occur but the antivirals are not reaching

49
Q

What is CD32a?

A

It is a controversial marker for latent HIV infected cells

50
Q

What are some new approaches to HIV therapy?

A

Better ART formulations etc. (e.g. slower release so its not daily doses)

Latency reversal - kick and kill

Targeting immune activation/ specific immunosuppression

Using the host: making the virus visible to sensing

Broadly neutralising antibodies - as adjunct therapy/ replacement or induced by antigens

Molecular Basis of Disease (28 decks)

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