Back From 2012 CROI
The 2012 Retroviruses Conference took place in Seattle, 5-8 March. Among several oral and poster sessions focusing on HIV reservoirs, HIV latency, HIV eradication, and acute HIV infection, we have selected some studies. As there is a wide coverage of this meeting everywhere, and most oral sessions are broadcasted on the CROI website, we limited our report to new data and comments on old ones.
The topic of HIV persistence was clearly at the front row during this last CROI.
However, most data reported were already presented at the last "HIV Persistence Workshop" in St Maartin 3 months back and were widely presented on this website.
SAHA Reactivates Latent HIV-1 in vivo
David Margolis (abstract 157 LB) presented the latest results of his ongoing trial testing the effect of a single 400 mg dose of SAHA (vorinostat) on the level of cell-associated full-length HIV RNA quantified specifically in resting CD4 T cells. He now has data on 6 patients (compared to 4 in St Maartin) and see a mean induction of 4.8 fold (range: 1.5 - 10) and an increase in histones acetylation at time +8 hours after administration.
However, no changes where found in terms of residual viremia with the single copy assay. During the discussion, Margolis told that it appears to be no difference in cell-associated full-length HIV RNA induction between TCM and TTM.
Sharon Lewin (abstract 106) is also conducting a study with SAHA, which consists in a 14-day administration period. She has already enrolled 9 patients with a median CD4 cell count of 710/mm3, a median duration of suppression on ART of 7.4 years. All were on a nNRTI regimen. Although no efficacy data on the reservoir were presented, she said that no changes in viral load and CD4 cell counts were found over a period of 84 days of follow up in 5 patients. Reversible gut side effects were observed. No change in T cell activation was found.
Purging will Need to Reactivate Latent HIV but also Help these Cells Die
In an interesting in vitro experiment Liang Shan (Abstract 153) from the Siliciano group isolated PBMCs from patients with undetectable viremia, treated them with SAHA and ART, and isolated resting CD4+ T cells. They were unable to measure any decrease in the reservoir because these cells were not killed by the viral cytopathic effect.
At a second visit they isolated autologous CD8 T cells from patients and put them in contact with cells treated with SAHA. After 8 days, around half of the cells were still alive.
They concluded that after reactivating latent HIV the viral cytopathic effect is insufficient and the CTL response is defective.
The Weird Rapid Effect of Disulfiram
During a themed discussion Adam Spivack (abstract 369) from Deeks group showed the data with disulfiram, which were also presented as poster. During a 14-day administration period of disulfiram at 500 mg/day, no significant changes in the reservoir size were found (IUPM) but an increase in viremia was observed in a subset of cases with the single copy assay. In 8 patients who were monitored close to the first dose of disulfiram, a statistically significant increase (4.5 fold, range: 1.4-14.8) was found within the first hours following the first administration. This increase remained <50 copies/ml in all but 1 case.
The authors did not have yet the results of the genetic analysis of these "small blips", did not present data on adherence or pharmacologic interactions between ARVs and disulfiram, and were unable to demonstrate that these results were not due to the variability of the single copy assay.
Nothing New with Zinc Finger Nucleases
Pablo Tebas (abstract 155) presented the same data repeatedly shown for 6 months since the last ICAAC.
Even if "patient 205" who was already heterozygote for the CCR5 delta 32 mutation became homozygote and was able to contain his viral load during the treatment interruption period, nothing new or updated was showed.
Anti-PD-1 Antibodies in Macaques infected with SIV
A new study was presented by Vijayakumar Velu (abstract 158 LB) from Emory University testing anti-PD-1 antibodies in SIV-infected macaques.
In vitro, anti-PD-1 antibodies were able to increase T cell proliferation and function and to decrease viral replication.
In a first experiment, macaques received anti-PD-1 antibodies at days 0, 3, 7 and 10 and an increased expansion of Gag specific CD8 T cells was observed.
In a second experiment, macaques received ART from week 16 to week 37 (n = 10) followed (n = 6) by anti-PD-1 antibodies beginning at week 41 for 6 doses of 3 mg/kg/dose.
Expression of PD-1 was 94% before ART, 52% on ART and 82% after ART cessation.
Anti-PD-1 antibodies blunted re-emerging viremia in a subset of animals but there were also non responders. SIV specific CD8 T cell quality (but not number) increased after anti-PD-1 antibodies. An increase in CD28 expression and CD127 expression was also found on SIV specific CD8 cells. The homing potential (CCR7) of CD8 T cells was also increased.
The "Super" Tenofovir
Peter Ruane (abstract 103) showed data proving that the new prodrug GS-7340 is superior to Tenofovir Disoproxil Fumarate (300 mg) at either 25 or 40 mg in a 10-day monotherapy study. The 40 mg dose induced the most important viral load decrease and produced a 20 fold increase in the intra cellular levels of the active drug.
The Gut Flora at Acute HIV Infection
An original study by Josué Perez Santiago (abstract 546) analysed the gut flora (pyrosequencing of 16s rDNA) at acute HIV infection and during follow up (n = 7). Lactobacillales, Enterobacteriales, Oceanospirillales and Neisseriales showed a positive correlation with CD4% while Clostridiales showed a negative correlation at baseline. Bacterial populations in the gut varied more between patients than within a patient over time. Although Lactobacillales exhibited the strongest correlation at baseline with CD4%, there was no longitudinal trend once ART was initiated. During eraly HIV infection (2-11 weeks) that is not treated, the correlation between CD4% and specific populations were robust, but while ART increased CD4% it did not show a specific trend of bacterial population longitudinally.
Key words: HDAC inhibitors, HIV cure, HIV persistence, zinc finger nucleases