title: The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.
abstract: Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8+ T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8+ T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8+ T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.
authors.affiliation: Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Walker-Sperling
authors.affiliation: Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pohlmeyer
authors.affiliation: Division of Biostatistics and Epidemiology, Paul L. Foster School of Medicine, El Paso, TX, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Tarwater
authors.affiliation: Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, USA. Electronic address: jblanks@jhmi.edu.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Blankson
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D054713:Bryostatins / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D015234:HLA-A Antigens / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019562:Viral Load; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D015415:Biomarkers; D054713:Bryostatins; D016207:Cytokines; D047630:Depsipeptides; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D011948:Receptors, Antigen, T-Cell; C046785:bryostatin 1; C087123:romidepsin
keywords: CD8+ T cells; Elite controllers; Elite suppressors; Eradication; HIV-1; Latency reversal agents