Flashcards in Approaches towards a cure for HIV Deck (36):
Why is a cure for HIV needed?
needs to be provided lifelong; global instability of funding etc; ART drug resistance; ART toxicity
Where is the HIV reservoir focused?
lymphoid tissue; lymph nodes; GALt; GU tract and brain
What are the ways of measuring HIV reservoir?
total HIV DNA; 2-LTR circles; integrated DNA infecitous units
How does the integrated DNA infectious units assay work?
activate cells and see if they can replicate virus
What is the problem with the total HIV DNA assay?
doesn't reflect replication competent virus but is still the most reproducible measure used in many studies
What is the most clinicalyl important outcome for HIV remission/cure?
viral control off ART
What are the ways of measuring viral control off ARt?
time to viral rebound; allow viral rebound and look fro length of potential control; allow to reach a new set point
When does viral rebound usually happen after ART interruption?
within 7-30 days
What are the questions surrounding ART interruption study designs?
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
What is a functional cure?
host control of viral replication without continued treatment; immune function restored and stabilised; HIV-induced inflammation reduced; risk of transmission to others reduced
What are hte 4 main approaches to cure HIV?
inhibit residual replication; immune modulation; shock and kill; gene therapy
What is the goal of inhibiting residual replication?
limiting the size of HIV reservoir below a threshold- enhanced cART and tissue penetration
What is the gaol of immune modulation strategy?
make the immune response able to recognise and remove HIV infected cells
What are the methods of immune modulation?
therapeutic vaccine; broadly neutralising antibodies
What is the strategy with gene therapy?
modify gene expression of latently infected cells to either lock down viral transcription or kill HIV infected reservoir cells
What have been the results of intensifying ART by additional ART agents?
after adding CCR5 inhibitor no impact on total HIV DNA; no impact with adding extra ART
What is the hypothesis with starting ARt in acute infection?
HIV reservoir in acute infection is most homogenous, smallest size and maybe easiest to influence
What is the result of initiating ART acutely vs in chronic infection?
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
What does total HIV DNA predict?
time to viral rebound after treatment interruption
What is thought to be the reason for very early ART initiation not conferring post treatment control?
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
what is the prupose of giving anti-PD1 to treat HIV patients
prevents immune exhaustion
What is the hypothesis behind broadly neutralising antibodies reducing HIV reservoirs?
block cell-cell spread of HIV; promote ADCC; antibody-dependent phagocytosis and complement fixation; antibody-antigen compelxes activate DCs to enhance antigen presentation function
What have been results of therapetuic T cell vaccine studies?
have had no impact on the HIV reservoir or lower viral rebound after ARt interruption
What is the theory behind DC-primed vaccines?
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
What was the result of DC-primed vaccination?
rapid viral rebound after vaccination and aRT interruption
What are the 5 key bNAb binding sites on the HIV envelope?
Cd4-binding site; V1/V2; V3; gp120/gp41 interface and MPER
What happened when Bnabs were given to viraemic patients prior to starting ARt?
acted as antivirlas and reduced HIV viral load by 2.5 logs
What was the effect of giving Bnabs to patients during treatment interruption?
up to 19 week delay in rebound vs historical avergae of 2.6 weeks
what caused rebounds in patients given bnabs during treatment interruption?
escape variants or once antibody levels had dropped
What is the hypothesis with latency reversing agents?
force viral transcription from latently infected cells to induce cell death and reduce the size of hte reservoir
How do histone deacetylases inhibit HIV expression?
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
Give an example of a histone deactylase inhibitor?
What were the resutls of a study comparing ART vs ART+ vorinostat +HIV vaccine?
no difference in total HIV DNA or viral outgrowth
What provides hope for the kick and kill approach?
study in rhesus monkeys with a TLR7 agonist and V3 bnab substantially delayed and controlled viral replication after cessation of ARt
What is the novel gene-editing technique capable of disrupting HIV-integrated genomces?