Bryostatin-1 synergizes with histone deacetylase inhibitors to reactivate HIV-1 from latency.
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 up-regulation 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.
Pérez
Moisés
M
Departamento de Biología Celular, Fisiología e Inmunología, Córdoba, Spain.
de Vinuesa
Amaya García
AG
Sanchez-Duffhues
Gonzalo
G
Marquez
Nieves
N
Bellido
M Luz
ML
Muñoz-Fernandez
M Angeles
MA
Moreno
Santiago
S
Castor
Trevor P
TP
Calzado
Marco A
MA
Muñoz
Eduardo
E
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D054713:Bryostatins / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D015536:Down-Regulation; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011533:Proviruses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015854:Up-Regulation; D017735:Virus Latency / Q000187:drug effects*
D019380:Anti-HIV Agents; D054713:Bryostatins; D015704:CD4 Antigens; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D019718:Receptors, CXCR4; C046785:bryostatin 1; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases