More on Maraviroc and HIV Reservoirs
This report is part of a series of focused summaries from the “5th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies” held in St Maarten, December 6-9, 2011. The two presentations reported were given by Doctor Beatriz Hernandez from Santiago Moreno group in Madrid and Maria Carmen Puertas from Bonaventura Clotet Group in Barcelona.
Is Maraviroc an anti-latency Agent?
This is the provocative question raised by Beatriz Hernandez presentation who suggested that Maraviroc can activate NFkB in patients regardless of the tropism of their infecting virus.
In their recently reported trial (1) of Maraviroc intensification, the authors observed a transient increase in 2-LTR circles (figure 1).
They therefore tried to evaluate the activation by Maraviroc of intracellular CCR5 signaling pathways leading to HIV-1 transcription in resting and activated CD4 T cells obtained from HIV-1 infected patients treated with Maraviroc.
The protocol, named “TROPISMCV” (NCT01060618) included naïve HIV-infected patients with CCR5-tropic and non-CCR5 tropic viruses, who received a 10 day monotherapy period of maraviroc.
PBMCs were isolated by Ficoll-Hypaque gradient from nine patients, bearing R5 (n=6) and D/M (n=3) tropic viruses. Activated and resting CD4 T cells were separated by magnetic beads coupled to monoclonal antibodies (MACS® Technology) by negative selection. Aliquots of 5 million-cells were frozen. Nuclear proteins were obtained using the Actif Motif Nuclear Extract KitTM.
Activity of NF-kB was detected in 4/6 patients with R5 tropic viruses (figure 2).
…and in 2/3 patients with D/M tropic viruses (figure 3).
This effect may persist in resting cells after withdrawal of the drug in some patients.
No change in NFAT activity was found (data not shown).
The authors suggested that Maraviroc might therefore have some latency-purging effects, in addition to its designed antiviral ones.
Can Maraviroc Deplete HIV Reservoirs?
Doctor Puertas reported that MVC intensification of ART sped on the decay of HIV-1 DNA in PBMC of recently infected patients treated with TDF/FTC and RAL.
The “Maraviboost study” included 30 early (<6 months) HIV-1-infected patients with CCR5-using viruses who were randomly assigned to receive a Maravirov intensified therapy (n=15) or a standard ART containing TDF/FTC/RAL (n=15) for a year.
The primary endpoint was to evaluate the slope of decay of the size of latent reservoir by measuring:
- Plasma residual viremia (RNA)
- PBMCs reservoir: integrated/non integrated viral DNA
- Residual replication: episomal viral DNA (2LTR) in PBMCs
The mean time from infection was 4.3 months in the intensified group versus 4.6 in the standard ART group (p>0.7).
The mean CD4 cells were 421/mm3 in the intensified group versus 428 in the standard ART group (p>0.7).
The mean viral load was 5.1 log in the intensified group versus 4.8 in the standard ART group (p>0.9).
At the end of the study (week 48) residual viremia was similar in both groups (1.0 log copies/ml) with a mean 4 log decrease.
Total HIV-1 DNA in PBMC progressively decreased in both treatment groups.
No differences between groups neither at the baseline nor at week 48, but at week 24 the difference between groups was statistically significant, suggesting a relative delay in the decay of the total viral reservoir in the control group (figure 4).
Concerning integrated DNA, there were no significant differences between groups at any time point.
A transient increase in 2LTR circles was observed in both groups just after treatment initiation but, overall, 2LTR HIV were undetectable in 5 patients from each group at week 48.
Transient increase in 2LTR, indicative of recent infection events, decreases faster in the intensified group, suggesting that MRV intensification of a triple-drug therapy results in a faster control of viral replication (figure 5).
Gutiérrez C, et al. PLoS One. 2011;6(12):e27864. Epub 2011 Dec 8.
Key words: HIV latency, HIV reservoirs, maraviroc