title: Histone deacetylase inhibitor romidepsin inhibits de novo HIV-1 infections.
abstract: Adjunct therapy with the histone deacetylase inhibitor (HDACi) romidepsin increases plasma viremia in HIV patients on combination antiretroviral therapy (cART). However, a potential concern is that reversing HIV latency with an HDACi may reactivate the virus in anatomical compartments with suboptimal cART concentrations, leading to de novo infection of susceptible cells in these sites. We tested physiologically relevant romidepsin concentrations known to reactivate latent HIV in order to definitively address this concern. We found that romidepsin significantly inhibited HIV infection in peripheral blood mononuclear cells and CD4(+) T cells but not in monocyte-derived macrophages. In addition, romidepsin impaired HIV spreading in CD4(+) T cell cultures. When we evaluated the impact of romidepsin on quantitative viral outgrowth assays with primary resting CD4(+) T cells, we found that resting CD4(+) T cells exposed to romidepsin exhibited reduced proliferation and viability. This significantly lowered assay sensitivity when measuring the efficacy of romidepsin as an HIV latency reversal agent. Altogether, our data indicate that romidepsin-based HIV eradication strategies are unlikely to reseed a latent T cell reservoir, even under suboptimal cART conditions, because romidepsin profoundly restricts de novo HIV infections.
authors.affiliation: Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark Aarhus Research Centre of Innate Immunology, Aarhus, Denmark.
authors.forename: Kasper L
authors.initials: KL
authors.lastname: Jønsson
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Vad-Nielsen
authors.affiliation: Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Kjær
authors.affiliation: Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark Aarhus Research Centre of Innate Immunology, Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Laustsen
authors.affiliation: Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Morten N
authors.initials: MN
authors.lastname: Andersen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital Skejby, Aarhus, Denmark Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark pauden@rm.dk mrj@biomed.au.dk.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: Institute of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark Aarhus Research Centre of Innate Immunology, Aarhus, Denmark pauden@rm.dk mrj@biomed.au.dk.
authors.forename: Martin R
authors.identifier: http://orcid.org/0000-0001-8847-9201
authors.initials: MR
authors.lastname: Jakobsen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009000:Monocytes / Q000821:virology; D061251:Primary Cell Culture; D017735:Virus Latency / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007371:Interferon-gamma; C087123:romidepsin