Bryostatin-1 Synergizes with Histone Deacetylase Inhibitors to Reactivate HIV-1 from Latency

Title: Bryostatin-1 Synergizes with Histone Deacetylase Inhibitors to Reactivate HIV-1 from Latency

Volume: 8 Issue: 6

Author(s): Moises Perez, Amaya Garcia de Vinuesa, Gonzalo Sanchez-Duffhues, Nieves Marquez, M. Luz Bellido, M. Angeles Munoz-Fernandez, Santiago Moreno, Trevor P. Castor, Marco A. Calzado and Eduardo Munoz

Affiliation:

Keywords: Bryostatins, HDACs, PKC, HIV-1 latency

Abstract: The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication on patients treated with HAART. It has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harboring latent HIV-1 provirus. Using Jurkat-LAT-GFP cells, a tractable model of HIV-1 latency, we have found that bryostatin-1 reactivates HIV-1 through a classical PKC-dependent pathway. Bryostatin-1 also activates MAPKs and NF-κB pathways and synergizes with HDAC inhibitors to reactivate HIV-1 from latency. Bryostatin-1 downregulates the expression of the HIV-1 co-receptors CD4 and CXCR4 and prevented de novo HIV-1 infection in susceptible cells. We applied proteomic methods to investigate major changes in protein expression in Jurkat-LAT-GFP under latency and reactivation conditions. We identified upregulation of proteins that may be involved in the innate anti-HIV-1 response (NKEF-A and MHD2) and in different cell functions (i.e. cofilin-1 and transgelin-2) of the host cells. PKC agonists may represent a valuable pharmacological approach to purge latent HIV from cellular reservoirs and at the moment, the only clinically available PKC agonist is bryostatin-1. This drug has been tested in numerous clinical trials and its pharmacokinetics and toxicity in humans is well known. Moreover, bryostatin-1 potently synergizes with other HDAC inhibitors commonly used in the medical practice such as valproic acid. Therefore, bryostatin-1, alone or in combination with HDAC inhibitors, could be used in HAART treated patients to validate the hypothesis that reactivating HIV-1 from latency could purge HIV-1 reservoirs.

Cite this article as:

Perez Moises, de Vinuesa Garcia Amaya, Sanchez-Duffhues Gonzalo, Marquez Nieves, Bellido Luz M., Munoz-Fernandez Angeles M., Moreno Santiago, Castor P. Trevor, Calzado A. Marco and Munoz Eduardo, Bryostatin-1 Synergizes with Histone Deacetylase Inhibitors to Reactivate HIV-1 from Latency, Current HIV Research 2010; 8 (6) . https://dx.doi.org/10.2174/157016210793499312