Professor of Medicine The Johns Hopkins University School of Medicine Baltimore Maryland Update on HIV Cure Research FORMATTED 111715 New Orleans Louisiana December 1517 2015 Slow decay of the reservoir ID: 921046
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Slide1
Robert F. Siliciano, MD, PhDProfessor of MedicineThe Johns Hopkins University School of MedicineBaltimore, Maryland
Update on HIV Cure Research
FORMATTED: 11/17/15
New Orleans, Louisiana: December 15-17, 2015
Slide2Slow decay of the reservoir
Siliciano et al., Nature Med., 2003
Crook et al, JID 2015
t
1/2
= 43 months
t
1/2
= 44 months
Slide3Approaches to HIV cure
Gene Rx
Prevent reactivation
†
Induce elite control
TCR pathway agonists
LRAs
(
HDACi
)
†
†
†
Shock and kill
Slide4Current status of LRA trials
TCR pathway agonists
LRAs
(
HDACi
)
†
†
†
Numerous LRAs identified in studies with transformed cell lines and primary T cell model systems
Few shown to work
ex vivo
with cells from patients
In clinical trials, no reduction in the reservoir yet demonstrated
Some evidence for slight transient increases in plasma HIV RNA after LRA treatment (
romidepsin
,
panobinostat
, TLR7 agonist)
In clinical trials, evidence for increases in cell-associated HIV RNA (
Archin
et al.)
Slide5Assays for latent HIV
TCR
agonist
Viral outgrowth
assay (VOA)
DNA PCR
PCR for
proviral
DNA
Measure intracellular
HIV RNA
Induction of HIV RNA
TCR
agonist
Measure
virion
release
Induction of
virion
production
TCR
agonist
Slide6Take home points
DNA PCR assays widely used for reservoir analysis mainly defect grossly defective proviruses
The quantitative viral outgrowth assay remains the best available assay for the latent
reservoir, but better assays are urgently needed.
There is no clinical assay for the latent reservoir
Other approaches: transient blips following LRA administration, time to rebound after ART interruption
Slide7Time to rebound
Hill et al, PNAS 2014
Time to rebound
Log reduction in
latent reservoir
1 wk
1 mo
10 yr
1 yr
3 mo
Lifetime
6
3
1
2
5
4
Berlin pt.
Boston
pt. B
Boston
pt. A
Chun et al.
Miss.
baby
Slide8Time Post Infection
(weeks) (years)
1,000,000
100,000
10,000
1000
100
Plasma HIV RNA (copies/ml)
cART
Therapeutic vaccination
cLRAs
What will cure look like?