title: Administration of Panobinostat Is Associated with Increased IL-17A mRNA in the Intestinal Epithelium of HIV-1 Patients.
abstract: Intestinal CD4(+) T cell depletion is rapid and profound during early HIV-1 infection. This leads to a compromised mucosal barrier that prompts chronic systemic inflammation. The preferential loss of intestinal T helper 17 (Th17) cells in HIV-1 disease is a driver of the damage within the mucosal barrier and of disease progression. Thus, understanding the effects of new therapeutic strategies in the intestines has high priority. Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are actively under investigation as potential latency reversing agents in HIV eradication studies. These drugs have broad effects that go beyond reactivating virus, including modulation of immune pathways. We examined colonic biopsies from ART suppressed HIV-1 infected individuals (clinicaltrials.gov: NCT01680094) for the effects of panobinostat on intestinal T cell activation and on inflammatory cytokine production. We compared biopsy samples that were collected before and during oral panobinostat treatment and observed that panobinostat had a clear biological impact in this anatomical compartment. Specifically, we observed a decrease in CD69(+) intestinal lamina propria T cell frequency and increased IL-17A mRNA expression in the intestinal epithelium. These results suggest that panobinostat therapy may influence the restoration of mucosal barrier function in these patients.
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark.
authors.forename: Ane
authors.initials: A
authors.lastname: Bjerg Christensen
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Dige
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Vad-Nielsen
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark.
authors.forename: Christel R
authors.initials: CR
authors.lastname: Brinkmann
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Mia
authors.initials: M
authors.lastname: Bendix
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark ; Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Østergaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark ; Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Tolstrup
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark ; Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Ole S
authors.initials: OS
authors.lastname: Søgaard
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rasmussen
authors.affiliation: Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark ; Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Randel Nyengaard
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8000 Aarhus, Denmark ; Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Agnholt
authors.affiliation: Department of Infectious Diseases, Aarhus University Hospital, 8200 Skejby, Denmark ; Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark ; Aarhus Institute for Advanced Studies, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Paul W
authors.identifier: 0000-0003-2458-8147
authors.initials: PW
authors.lastname: Denton
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000328:Adult; D005786:Gene Expression Regulation; D015497:HIV-1; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology*; D008213:Lymphocyte Activation; D000077767:Panobinostat; D012333:RNA, Messenger / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508717:IL17A protein, human; D007211:Indoles; D020381:Interleukin-17; D012333:RNA, Messenger; D007371:Interferon-gamma; D000077767:Panobinostat