title: CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies.
abstract: Latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACi), are being investigated as a strategy to eliminate latency in HIV-infected patients on suppressive antiretroviral therapy. The effectiveness of LRAs in activating latent infection in HIV strains derived from the central nervous system (CNS) is unknown. Here we show that CNS-derived HIV-1 strains possess polymorphisms within and surrounding the Sp transcription factor motifs in the long terminal repeat (LTR). These polymorphisms result in decreased ability of the transcription factor specificity protein 1 to bind CNS-derived LTRs, reducing the transcriptional activity of CNS-derived viruses. These mutations result in CNS-derived viruses being less responsive to activation by the HDACi panobinostat and romidepsin compared with lymphoid-derived viruses from the same subjects. Our findings suggest that HIV-1 strains residing in the CNS have unique transcriptional regulatory mechanisms, which impact the regulation of latency, the consideration of which is essential for the development of HIV-1 eradication strategies.
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia.
authors: L R
authors: LR
authors: Gray
authors: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
authors: D
authors: D
authors: Cowley
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.
authors: C
authors: C
authors: Welsh
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.
authors: H K
authors: HK
authors: Lu
authors: Departments of Neurology, Immunology and Infectious Diseases and Peter Duncan Neurosciences Unit, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, New South Wales, Australia.
authors: B J
authors: BJ
authors: Brew
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.|Infectious Diseases, Alfred Hospital, Melbourne, Victoria, Australia.
authors: S R
authors: SR
authors: Lewin
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors: S L
authors: SL
authors: Wesselingh
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia.|School of Applied Sciences and Program in Metabolism, Exercise and Disease, Health Initiatives Research Institute, RMIT University, Melbourne, Victoria, Australia.|Department of Medicine, Monash University, Melbourne, Victoria, Australia.
authors: P R
authors: PR
authors: Gorry
authors: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia.|Department of Medicine, Monash University, Melbourne, Victoria, Australia.|Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
authors: M J
authors: MJ
authors: Churchill
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism / Q000821:virology*; D015496:CD4-Positive T-Lymphocytes; D002490:Central Nervous System / Q000378:metabolism; D015331:Cohort Studies; D047630:Depsipeptides / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D011110:Polymorphism, Genetic; D020079:Terminal Repeat Sequences; D015533:Transcriptional Activation; D017735:Virus Latency / Q000187:drug effects
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; C087123:romidepsin