title: Specific Elimination of Latently HIV-1 Infected Cells Using HIV-1 Protease-Sensitive Toxin Nanocapsules.
abstract: Anti-retroviral drugs suppress HIV-1 plasma viremia to undetectable levels; however, latent HIV-1 persists in reservoirs within HIV-1-infected patients. The silent provirus can be activated through the use of drugs, including protein kinase C activators and histone deacetylase inhibitors. This "shock" approach is then followed by "kill" of the producing cells either through direct HIV-1-induced cell death or natural immune mechanisms. However, these mechanisms are relatively slow and effectiveness is unclear. Here, we develop an approach to specifically target and kill cells that are activated early in the process of virus production. We utilize a novel nanocapsule technology whereby the ricin A chain is encapsulated in an inactive form within a polymer shell. Specificity for release of the ricin A toxin is conferred by peptide crosslinkers that are sensitive to cleavage by HIV-1 protease. By using well-established latent infection models, J-Lat and U1 cells, we demonstrate that only within an HIV-1-producing cell expressing functional HIV-1 protease will the nanocapsule release its ricin A cargo, shutting down viral and cellular protein synthesis, and ultimately leading to rapid death of the producer cell. Thus, we provide proof of principle for a novel technology to kill HIV-1-producing cells without effects on non-target cells.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Biomolecular and Chemical Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biomolecular and Chemical Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biomolecular and Chemical Engineering, University of California Los Angeles, Los Angeles, California, United States of America.|California NanoSystems Institute (CNSI), University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Hematology-Oncology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kamata
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California, University of California Los Angeles, Los Angeles, California, United States of America.|UCLA AIDS Institute, Los Angeles, California, United States of America.
authors.forename: Irvin S Y
authors.initials: IS
authors.lastname: Chen
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002619:Chemical Warfare Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006678:HIV / Q000187:drug effects* / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D053769:Nanocapsules / Q000737:chemistry*; D012276:Ricin / Q000494:pharmacology*; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D002619:Chemical Warfare Agents; D004791:Enzyme Inhibitors; D053769:Nanocapsules; D012276:Ricin; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1