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Module 2 > Approaches towards a cure for HIV > Flashcards

Approaches towards a cure for HIV Flashcards

1
Q

Why is a cure for HIV needed?

A

needs to be provided lifelong; global instability of funding etc; ART drug resistance; ART toxicity

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2
Q

Where is the HIV reservoir focused?

A

lymphoid tissue; lymph nodes; GALt; GU tract and brain

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3
Q

What are the ways of measuring HIV reservoir?

A

total HIV DNA; 2-LTR circles; integrated DNA infecitous units

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4
Q

How does the integrated DNA infectious units assay work?

A

activate cells and see if they can replicate virus

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5
Q

What is the problem with the total HIV DNA assay?

A

doesn’t reflect replication competent virus but is still the most reproducible measure used in many studies

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6
Q

What is the most clinicalyl important outcome for HIV remission/cure?

A

viral control off ART

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7
Q

What are the ways of measuring viral control off ARt?

A

time to viral rebound; allow viral rebound and look fro length of potential control; allow to reach a new set point

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8
Q

When does viral rebound usually happen after ART interruption?

A

within 7-30 days

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9
Q

What are the questions surrounding ART interruption study designs?

A

how to do it safely; how frequently to test viral load; how to test viral load; risks of viral transmission; how long to wait before treatment re-initiation

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10
Q

What is a functional cure?

A

host control of viral replication without continued treatment; immune function restored and stabilised; HIV-induced inflammation reduced; risk of transmission to others reduced

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11
Q

What are hte 4 main approaches to cure HIV?

A

inhibit residual replication; immune modulation; shock and kill; gene therapy

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12
Q

What is the goal of inhibiting residual replication?

A

limiting the size of HIV reservoir below a threshold- enhanced cART and tissue penetration

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13
Q

What is the gaol of immune modulation strategy?

A

make the immune response able to recognise and remove HIV infected cells

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14
Q

What are the methods of immune modulation?

A

therapeutic vaccine; broadly neutralising antibodies

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15
Q

What is the strategy with gene therapy?

A

modify gene expression of latently infected cells to either lock down viral transcription or kill HIV infected reservoir cells

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16
Q

What have been the results of intensifying ART by additional ART agents?

A

after adding CCR5 inhibitor no impact on total HIV DNA; no impact with adding extra ART

17
Q

What is the hypothesis with starting ARt in acute infection?

A

HIV reservoir in acute infection is most homogenous, smallest size and maybe easiest to influence

18
Q

What is the result of initiating ART acutely vs in chronic infection?

A

rate of decline in total HIV DNA is nehanced after starting ART when started in acute infection and absolute level of total DNA achieved on stable therapy is lower

19
Q

What does total HIV DNA predict?

A

time to viral rebound after treatment interruption

20
Q

What is thought to be the reason for very early ART initiation not conferring post treatment control?

A

in Thai study, 8 individuals started in first 2 weeks of infection did not have any improved PTC- maybe as prior to antibody development, which didn’t allow the immune system to develop and be able to control viral rebound

21
Q

what is the prupose of giving anti-PD1 to treat HIV patients

A

prevents immune exhaustion

22
Q

What is the hypothesis behind broadly neutralising antibodies reducing HIV reservoirs?

A

block cell-cell spread of HIV; promote ADCC; antibody-dependent phagocytosis and complement fixation; antibody-antigen compelxes activate DCs to enhance antigen presentation function

23
Q

What have been results of therapetuic T cell vaccine studies?

A

have had no impact on the HIV reservoir or lower viral rebound after ARt interruption

24
Q

What is the theory behind DC-primed vaccines?

A

monocyte derived DCs loaded ex vivo with RNA encoding HIV antigens as are potent APCs and induce T cells reponses- has been successful in chronic infections and acancer

25
Q

What was the result of DC-primed vaccination?

A

rapid viral rebound after vaccination and aRT interruption

26
Q

What are the 5 key bNAb binding sites on the HIV envelope?

A

Cd4-binding site; V1/V2; V3; gp120/gp41 interface and MPER

27
Q

What happened when Bnabs were given to viraemic patients prior to starting ARt?

A

acted as antivirlas and reduced HIV viral load by 2.5 logs

28
Q

What was the effect of giving Bnabs to patients during treatment interruption?

A

up to 19 week delay in rebound vs historical avergae of 2.6 weeks

29
Q

what caused rebounds in patients given bnabs during treatment interruption?

A

escape variants or once antibody levels had dropped

30
Q

What is the hypothesis with latency reversing agents?

A

force viral transcription from latently infected cells to induce cell death and reduce the size of hte reservoir

31
Q

How do histone deacetylases inhibit HIV expression?

A

catalyse de-acetylation of histone tails and keep chromatin in a compacted state, inhibtion of these histone deacetylases promotes histone acetylation leading to relaxation of chromatin and initiation of transcription

32
Q

Give an example of a histone deactylase inhibitor?

A

vorinostat

33
Q

What were the resutls of a study comparing ART vs ART+ vorinostat +HIV vaccine?

A

no difference in total HIV DNA or viral outgrowth

34
Q

What provides hope for the kick and kill approach?

A

study in rhesus monkeys with a TLR7 agonist and V3 bnab substantially delayed and controlled viral replication after cessation of ARt

35
Q

What is the novel gene-editing technique capable of disrupting HIV-integrated genomces?

A

CRISPR-Cap9 technique

36
Q

What is a danger with gene editing?

A

what is the possibility of deleting the wrong genes?

Module 2 (38 decks)

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