Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes
| Autor: | Stefanie Mueller, Rachel O’Connor, Richard Bradley Jones, Maria Hottelet Foley, Gregory L. Szeto, Darrell J. Irvine, Mathias Lichterfeld, Colin Kovacs, Mario A. Ostrowski, Bruce D. Walker, Alicja Trocha, Dan Karel |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Ragon Institute of MGH, MIT and Harvard, Koch Institute for Integrative Cancer Research at MIT, Jones, Richard Bradley, O'Connor, Rachel, Mueller, Stefanie, Foley, Maria Hottelet, Szeto, Gregory Lee, Karel, Dan, Trocha, Alicja, Irvine, Darrell J., Walker, Bruce D. |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cytotoxicity
Immunologic Viral Diseases Indoles medicine.medical_treatment HIV Infections Clinical immunology Hydroxamic Acids Virus Replication Romidepsin chemistry.chemical_compound White Blood Cells Immunodeficiency Viruses Animal Cells Depsipeptides Panobinostat Medicine and Health Sciences Cytotoxic T cell lcsh:QH301-705.5 T Cells HIV immunopathogenesis 3. Good health Cytokine Infectious Diseases Medical Microbiology Viral Pathogens Cellular Types medicine.drug Research Article lcsh:Immunologic diseases. Allergy Cell Survival Immune Cells Immunology Biology Microbiology Immunomodulation Immune system Virology Genetics medicine Humans Molecular Biology Microbial Pathogens Cell Proliferation Depsipeptide Blood Cells Biology and life sciences HIV Cell Biology Histone Deacetylase Inhibitors CTL chemistry lcsh:Biology (General) Parasitology Histone deacetylase lcsh:RC581-607 T-Lymphocytes Cytotoxic |
| Zdroj: | Public Library of Science PLoS Pathogens PLoS Pathogens, Vol 10, Iss 8, p e1004287 (2014) |
| Popis: | Resting memory CD4[superscript +] T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia. Ragon Institute of MGH, MIT, and Harvard Canadian Institutes of Health Research (Banting Fellow) Ontario HIV Treatment Network (Junior Investigator) |
| Databáze: | OpenAIRE |
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