title: Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.
abstract: Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia. lachlang@burnet.edu.au.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia. lachlang@burnet.edu.au.
authors.forename: Lachlan R
authors.initials: LR
authors.lastname: Gray
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Hung
authors.initials: H
authors.lastname: On
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Roberts
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.|Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Hao K
authors.initials: HK
authors.lastname: Lu
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.|Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moso
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Raison
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Papaioannou
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Cheng
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Ellett
authors.affiliation: Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.|Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jacobson
authors.affiliation: Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.|Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Damian F J
authors.initials: DF
authors.lastname: Purcell
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Steve L
authors.initials: SL
authors.lastname: Wesselingh
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.|Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia.|Department of Medicine, Monash University, Melbourne, VIC, Australia.|School of Applied Sciences, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia.|Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.affiliation: Centre for Biomedical Research, Burnet Institute, 85 Commercial Rd, Melbourne, 3004, VIC, Australia. churchil@burnet.edu.au.|Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia. churchil@burnet.edu.au.|Department of Microbiology, Monash University, Clayton, VIC, Australia. churchil@burnet.edu.au.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D001381:Azepines / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D005333:Fetus; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D000077767:Panobinostat; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects* / Q000235:genetics; D017735:Virus Latency / Q000187:drug effects* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics; D000077337:Vorinostat
chemical_list: C561695:(+)-JQ1 compound; D000081:Acetamides; D001381:Azepines; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D010879:Piperazines; D014230:Triazoles; C002511:chaetocin; D000077337:Vorinostat; D000077767:Panobinostat; C087123:romidepsin; C014026:hexamethylene bisacetamide; D004221:Disulfiram
keywords: CNS; HIV-1; Latency; Latency-reversing agents; Reservoirs; Toxicity