title: A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes.
abstract: Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8+ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8+ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8+ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8+ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8+ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam3CSK4. In contrast, we did not observe CD8+ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist 'ALT-803', an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8+ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8+ T-cells in HIV eradication strategies.
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.|Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America.|Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, D.C., United States of America.
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mueller
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: O'Connor
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Rimpel
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Karel
authors.affiliation: Altor BioScience Corporation, Miramar, Florida, United States of America.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Altor BioScience Corporation, Miramar, Florida, United States of America.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.|Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, D.C., United States of America.
authors.forename: Allison S
authors.initials: AS
authors.lastname: Thomas
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.|Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Whitney
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: So-Yon
authors.initials: SY
authors.lastname: Lim
authors.affiliation: The Maple Leaf Medical Clinic, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.affiliation: The Maple Leaf Medical Clinic, Toronto, Ontario, Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Benko
authors.affiliation: Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, D.C., United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Karandish
authors.affiliation: Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, D.C., United States of America.
authors.forename: Szu-Han
authors.initials: SH
authors.lastname: Huang
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Buzon
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Alivelu
authors.initials: A
authors.lastname: Irrinki
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Murry
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Tsai
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Yu
authors.affiliation: Gilead Sciences, Foster City, California, United States of America.
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Alicja
authors.initials: A
authors.lastname: Trocha
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Li Ka Shing Medical Institute, St. Michael's Hospital, Toronto, Ontario, Canad.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America.|Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.|Department of Biological Engineering, MIT, Cambridge, Massachusetts, United States of America.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.affiliation: The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America.|Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*
chemical_list: C582303:ALT-803; D000998:Antiviral Agents; D011506:Proteins; D011993:Recombinant Fusion Proteins