title: Histone Deacetylase Inhibitors Enhance CD4 T Cell Susceptibility to NK Cell Killing but Reduce NK Cell Function.
abstract: In the search for a cure for HIV-1 infection, histone deacetylase inhibitors (HDACi) are being investigated as activators of latently infected CD4 T cells to promote their targeting by cytotoxic T-lymphocytes (CTL). However, HDACi may also inhibit CTL function, suggesting different immunotherapy approaches may need to be explored. Here, we study the impact of different HDACi on both Natural Killer (NK) and CTL targeting of HIV-1 infected cells. We found HDACi down-regulated HLA class I expression independently of HIV-1 Nef which, without significantly compromising CTL function, led to enhanced targeting by NK cells. HDACi-treated HIV-1-infected CD4 T cells were also more effectively cleared than untreated controls during NK co-culture. However, HDACi impaired NK function, reducing degranulation and killing capacity. Depending on the HDACi and dose, this impairment could counteract the benefit gained by treating infected target cells. These data suggest that following HDACi-induced HLA class I down-regulation NK cells kill HIV-1-infected cells, although HDACi-mediated NK cell inhibition may negate this effect. Our data emphasize the importance of studying the effects of potential interventions on both targets and effectors.
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Institute for Emerging Infections, The Oxford Martin School, Oxford, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pace
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Williams
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kurioka
authors.affiliation: Adaptimmune Ltd, Oxfordshire, United Kingdom.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Gerry
authors.affiliation: Adaptimmune Ltd, Oxfordshire, United Kingdom.
authors.forename: Bent
authors.initials: B
authors.lastname: Jakobsen
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Institute for Emerging Infections, The Oxford Martin School, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Nneka
authors.initials: N
authors.lastname: Nwokolo
authors.affiliation: Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Fox
authors.affiliation: Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fidler
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, United Kingdom.|Institute for Emerging Infections, The Oxford Martin School, Oxford, United Kingdom.|Oxford National Institute of Health Research Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Frater
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D017735:Virus Latency / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors