Targeting of Latent 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. This article recaps the presentation given by Professor Jerome Zack from David Geffen School of Medicine, UCLA, USA.
Professor Zack first recalled that HIV persistence during therapy is due to the existence of long-lived latently infected cells that are indistinguishable from normal cells (figure 1).
Stimulation of latently infected cells could activate the latent virus, leading to death by cytopathic effects or by CTL activity.
However, activators of HIV gene expression are not necessarily specific.
Ideal activators would increase viral gene expression without activating cell proliferation.
However bystander effects are likely from this approach.
Therefore, Professor Zack team is attempting to find ways to minimize bystander cell activation and identify more efficient activators, which may have improved tolerability profiles.
Bryostatin, first isolated from Bugula neritina , modulates PKC activity. Jerome Zack group recently reported (Kovochich et al, PLoS One, 2011) the successful loading of lipid nanoparticles with Bryostatin and Nelfinavir. These lipid particles were shown in vitro to both activate latent virus expression and inhibit viral spread (figure 2).
However, to be suitable clinical use, nanoparticles must be uniform in size, non-immunogenic, non-toxic and biocompatible. That is why Professor Zack had the idea to use natural occurring cell particle, called “Vaults”, which were first described in 1986 by biochimists at UCLA. Their function remains unknown and human cells each contain one million vaults, which are eukaryotic cell organelles. Vaults contain 3 proteins and RNA.
The structure of a vault at 3.5 Angstrom resolution is shown in figure 3.
The research team engineered vaults to include Bryostatin (figure 4) and found a positive effect in vitro on reactivation of latent HIV (figure 5).
This original approach, which is kind of a Trojan horse, is now tested in the BLT humanized mouse model may for assessing in vivo efficacy of this HIV latency purging strategy.
Key words: HIV cure, bryostatin, purge of HIV reservoirs, vaults