Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.

Autor:	Armani-Tourret M; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Gao C; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Hartana CA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Sun W; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Carrere L; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Vela L; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Hochroth A; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Bellefroid M; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Sbrolla A; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA., Shea K; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA., Flynn T; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA., Roseto I; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Rassadkina Y; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA., Lee C; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA., Giguel F; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Malhotra R; Division of Cardiology, Massachusetts General Hospital, Boston, MA 02114, USA., Bushman FD; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA., Gandhi RT; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA., Yu XG; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Kuritzkes DR; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Lichterfeld M; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: mlichterfeld@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Feb 29; Vol. 187 (5), pp. 1238-1254.e14. Date of Electronic Publication: 2024 Feb 17.
DOI:	10.1016/j.cell.2024.01.037
Abstrakt:	CD4 + T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses. Competing Interests: Declaration of interests D.R.K. discloses having received research funding and a speaker fee from Novartis. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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