A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes

PLoS Pathogens

Allison S. Thomas¹  James B. Whitney¹  Sara Karandish²  Szu-Han Huang²  Mathias Lichterfeld³  Rachel O’Connor⁴  Colin Kovacs⁴  Angela Tsai⁴  Jeffrey P. Murry⁴  Mario A. Ostrowski⁵  Alicja Trocha⁵  Darrell J. Irvine⁵  Hing C. Wong⁵  Bruce D. Walker⁵  Katherine Rimpel⁶  Stefanie Mueller⁶  Alivelu Irrinki⁷  Maria J. Buzon⁷  Derek D. Sloan⁸  R. Brad Jones⁸  Emily K. Jeng⁸  So-Yon Lim⁸  Romas Geleziunas⁸  Dan Karel⁸  Erika Benko⁸  Helen Yu⁸ 

[1] Altor BioScience Corporation, Miramar, Florida, United States of America;Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Medicine, University of Toronto, Toronto, Ontario, Canada;Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, D.C., United States of America;Gilead Sciences, Foster City, California, United States of America;Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts, United States of America;The Maple Leaf Medical Clinic, Toronto, Ontario, Canada;The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, United States of America

关键词: T cells;    Cytotoxic T cells;    HIV;    Flow cytometry;    Viral persistence;    latency;    Cell staining;    Enzyme-linked immunoassays;    HIV infections;   

DOI  :  10.1371/journal.ppat.1005545

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY