title: Activation of latent HIV using drug-loaded nanoparticles.
abstract: Antiretroviral therapy is currently only capable of controlling HIV replication rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T cells, which persists even in the presence of HAART. It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target and activate primary human CD4+ T-cells and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the HDAC inhibitor sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. Taken together these data demonstrate the ability of nanotechnological approaches to provide improved methods for activating latent HIV and provide key proof-of-principle experiments showing how novel delivery systems may enhance future HIV therapy.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Kovochich
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Marsden
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D054713:Bryostatins / Q000737:chemistry / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D005240:Feasibility Studies; D006678:HIV / Q000187:drug effects* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D054713:Bryostatins; D004337:Drug Carriers; D008055:Lipids; D011480:Protease Inhibitors; C054557:bryostatin 2