NIH HIV CURE 2014 MEETING (Part 2)
The NIH organized on October 15-17, 2014 a meeting intitled 'Strategies for an HIV Cure'.
This is the second edition of the meeting, the first one being held in November 2012. Its main instigator is Karl Salwedel from the NIH.
We propose below a summary of the main presentations. This is not an exhaustive report and we have had to make choices due to the quantity of data often presented in a very short time. Although, we did not insist on presentation which were quite the same as those shown a month ago at the Baltimore meeting (regarding them, please refer to the corresponding report).
The second day started with a presentation given by Robert Siliciano.
Using full length PCR and primers targeting both gag and Env, he found that only 3% of proviruses are intact.
The outgrowth assay underestimates the size of the reservoir (1/1 million cells), the PCR assays surestimates it (450/1 million cells) and the truth might be in between (15/1 million cells).
Regarding residual viremia, plasma clones wax and wane and a clone prevalent at a later time does not correspond to earlier clones.
Clearance of reactivated cells is obtained only in Elite Controllers as in chronic infection 100% of the epitopes are mutated, corresponding to CTL escape mutations.
Using modelization, he showed that at least a 3 log reduction in the reservoir is needed to get a 1 year delay in the rebound of viremia.
John Mellors then showed that persistant viremia on ART decreases of about 6% per year.
Nicolas Chomont detailed his TILDA assay.
TILDA stands for Tat/Rev Induced Limiting Dilution Assay.
It gives an estimation of the size of the reservoir in between DNA PCR and outgrowth assays.
TILDA is cheap (300 USD), rapid (>2 hours), sensitive (1.4 cell/million), only needs 10 ml of blood, and a version exists for SIV.
Matthew Strain showed that digital droplet PCR for DNA and RNA are equally sensitives.
Sharon Lewin presented results of Disulfiran in 3 cohorts of patients:
CA-US HIV RNA/million cells increased since day 0 (before starting Disulfiram) compared to 2 prior time points. No difference was found by the SCA. These results might be due to circadian changes in CLOCK proteins.
Paul Wender detailed the progress made for the synthesis of Prostatin (initially derived from a Samoan Tree bark) and Bryostatin (extracted from algae).
Richard Barnard from Merck screened 2.9 million compounds for their activity as rective agents and showed that only 16.1% were HDACi, the majority being of unknown mode of action.
Mathias Lichterfield reported a trial of panobinostat 3 times weekly. A decrease in proviral DNA was observed. 9 out of 15 patients agreed for ATI.
DNA preferentially decreased in IL28B 'CC' genotypes and correlated with the percentage of NK cells and pDC.
The afternoon of the second day was devoted to immune-based strategies.
Richard Koup talked about broadly neutralizing antibodies. He presented the design of a study in 4 groups of 6 monkeys:
-in ARV only
-on ARV + nAb VRCO
-on ARV + nAb VRCOO7521+PCT121
Lymph nodes DNA is planed to be measured.
Michael Farzan talked about adeno associated virus vectors (AAV).
Enhanced CD4-Ig are more potent that the best bnAb.
Galit Alter and Scott Koenig also detailed progress in antibodies for reservoir eradication.
The third morning was first dedicated to acute infection.
Deborah Persaud talked about HIV latency in perinatal infection. Starting ART early (>3 months) at acute infection is important as it is a time where there are mainly resting memory CD4+ T cells.
She descrobed 12 patients who received ART at the age of 2 months and are suppressed for 5.5 years:
-67% are antobody negative
-83% still have detectable replication competent HIV.
Four other patients treated at 0.5 - 2.6 months all are SCA negative, ELISA and Western blot negative, and non recoverable replication competent HIV.
Jintana Avanworanich presented her RV254/SEARCH010 study were 251 patients with acute HIV infection were included and 201 treated by ART. Mega-ART (including raltegravir) produced a more rapid decline in plasma viremia than ART until week 16 but the results in plasma suppression were the same in the 2 groups.
Fiebig stage I and III patients exhibited decreases in HIV DNA mainly due to integrated DNA.
15 LN biopsies were done and less fibrosis was found in Fiebig I than Fiebig III treated patients.
In addition, in Fiebig I patients there was a preservation of polufunctional gut Th17 cells.
Hiroyu Hatano talked about 'hyperacute' HIV infection. These are patients diagnosed very early as they are initially seen for PrEp.In SFO, 42 patients have been enrolled between July 2013 and October 2014 and 11 underwent colorectal biopsies.
She developped the case of patient 1 who was on PrEp with truvada and had 220 copies/ml of plasma HIV RNA 10 days post-infection. ART was started at day 18 and the follow-up is 12 months. HIV iRNA or DNA s undetectable in rectum, ileum, CSF, bone marrow.
The outgrowth assay and TILDA are negative.
Of note he is wild type on CCR5.
Finally, Dan Barouch went back on bnAb. The combination or Truvada and Dolutegravir started at day 3 in SIV-infected monkeys prevented the peak in viremia.
He presented a study of 6 months treatment:
-4 SHIV-infected monkeys with ART alone: all rebounded at ART cessation
-5 with ART + PGT121: 3/5 had a decrease in viral DNA and 3/5 experienced only blips (2) or no rebound (1) at ART cessation. However, antibodies against nbAb were generated.
Key words: HIV DNA, HIV cure, HIV persistence, HIV reservoirs, NIAID, NIH, acute HIV infection