Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States; Department of Medicine, University of California San Francisco, San Francisco, United States; Buck Institute for Research on Aging, Novato, United States
Matthew S Dahabieh
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States; Department of Medicine, University of California San Francisco, San Francisco, United States
Mohamed Abdel-Mohsen
University of California San Francisco, San Francisco, United States; Blood Systems Research Institute, San Francisco, United States; The Wistar Institute, Philadelphia, United States
Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden
Israel Tojal Da Silva
Laboratory of Molecular Immunology, The Rockefeller University, New York, United States; Laboratory of Computational Biology and Bioinformatics, International Research Center, Sao Paulo, Brazil
Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
Andrea Gramatica
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States; Department of Medicine, University of California San Francisco, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, United States
Department of Medicine, University of California San Francisco, San Francisco, United States
Warner C Greene
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States; Department of Medicine, University of California San Francisco, San Francisco, United States; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, United States
Satish K Pillai
University of California San Francisco, San Francisco, United States; Blood Systems Research Institute, San Francisco, United States
Gladstone Institute of Virology and Immunology, Gladstone Institutes, San Francisco, United States; Department of Medicine, University of California San Francisco, San Francisco, United States; Buck Institute for Research on Aging, Novato, United States
Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The ‘shock and kill’ approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4+ T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs. non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of ‘shock and kill’, and suggest the need to explore other strategies to control the latent HIV reservoir.
