Trojan Horse Against HIV
In an article published this month in PLoSone, a new strategy to activate latent HIV and deplete reservoirs is proposed. Nanoparticles containing Bryostatin, a NFkB activator, have been designed to target latently infected cells more precisely: the Trojan Horse strategy applied to HIV research...
The idea is quite interesting: encapsulate factors able to reactivate HIV from latency in nanoparticles capable to enhance delivery in tissues, brain, or even specific cells. In particular, liposomes offer a biodegradable vehicle which is capable of carrying a variety of substances to target sites either through passive or active targeting. The targeting strategy may help prevent toxicity due to generalized immune activation during efforts to purge latent HIV.
This work is published in the April 2011 issue of PLoSone by the California team of Jerome A. Zack (1).
Bryostatin has been demonstrated to activate latent HIV at nanomolar concentrations in vitro (2). Bryostatin-1 has been tested in clinical trials for anti-cancer properties. Bryostatin-2, which was used in this experiment, can also activate PKC at nanomolar concentration.
Bryostatin-2 was packaged in lipid nanoparticles (LNP-Bry) and tested in cell lines and in the SCID-hu (Thy/Liv) mouse model for HIV latency. LNP-Bry were non-toxic in all cell types including PBMCs.
One major potential of this construct is the possibility to incorporate both a latency activator and a protease inhibitor in the construct. This strategy may be particularly important if particles are developed to enter anatomical sites that are not easily penetrated by some antiretroviral drugs, like the brain. To this end, the authors incorporated nelfinavir in the LNP-Bry and the particle was capable in vitro both to stimulate latent virus and inhibit virus spread.
Finally, some selectivity can be added to this construct to minimize activation of other cells. The main problem is that latently-infected cells do not bear specific cell surface markers to identify them. However, the authors chose the CD4 receptor as the target and demonstrated that these particles were able to preferentially activate CD4+ cells. This was possible by coating the nanoparticles with anti-CD4 antibodies.
This original experiment therefore leads to the construction of a kind of Trojan Horse against HIV, able to target specifically different kind of cells, and both deliver anti-latency agents and antiretrovirals. A genious weapon in the battle against HIV persistence!
1-Kovochich M, Marsden MD, Zack JA. Activation of Latent HIV Using Drug-Loaded Nanoparticles. PLoS One 2011; 6(4): e18270
2-Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One 2010; 5(6): e11160.
Key words: Bryostatin, HIV purge, HIV reservoirs, anti-latency agents