HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat
| Autor: | Rosalie Bateson, John M. Coffin, Manoj K. Tripathy, Amanda M. Crooks, Joseph J. Eron, Angela D. M. Kashuba, Joann D. Kuruc, Douglas D. Richman, Elizabeth M. Anderson, Noelle P. Dahl, Kuo Hsiung Yang, Ronald J. Bosch, Matthew C. Strain, Mary F. Kearney, Kevin Robertson, Daria J. Hazuda, Nancy M. Archin, David M. Margolis |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male genetic structures Hydroxamic Acids Medical and Health Sciences Leukocytes Immunology and Allergy 2.2 Factors relating to the physical environment Viral Aetiology Pediatric education.field_of_study Vorinostat Histone deacetylase inhibitor Provirus Middle Aged Biological Sciences Long terminal repeat Infectious Diseases Blood 6.1 Pharmaceuticals HIV/AIDS RNA Viral HIV Long Terminal Repeat Infection medicine.drug Adult medicine.drug_class Population Mononuclear Clinical Trials and Supportive Activities histone Biology Microbiology Virus Major Articles and Brief Reports HDAC inhibitor Clinical Research medicine Genetics Humans education Transcription factor latency acetylation Evaluation of treatments and therapeutic interventions HIV DNA Virology Histone Deacetylase Inhibitors DNA Viral Leukocytes Mononuclear HIV-1 RNA sense organs |
| Zdroj: | Archin, Nancy M; Bateson, Rosalie; Tripathy, Manoj K; Crooks, Amanda M; Yang, Kuo-Hsiung; Dahl, Noelle P; et al.(2014). HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.. The Journal of infectious diseases, 210(5), 728-735. doi: 10.1093/infdis/jiu155. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/0rd3381n The Journal of infectious diseases, vol 210, iss 5 |
| DOI: | 10.1093/infdis/jiu155. |
| Popis: | Effective antiretroviral therapy allows human immunodeficiency virus (HIV)–infected individuals to live long and productive lives [1]. However, HIV infection remains incurable in part owing to the presence of quiescent, replication-competent provirus within a long-lived population of memory T cells, capable of reigniting new rounds of infection if therapy is interrupted. This latent pool of virus is established within days of infection and is refractory to the actions of the immune system or of current therapy [2–4]; thus, HIV infection will require lifetime treatment unless persistent, latent infection is purged. After integration of HIV DNA into the cellular genome, the HIV long terminal repeat promoter exists in a nucleosome-bound conformation and is transcriptionally silent without stimulation of the infected cell. Studies by several laboratories have suggested that multiple mechanisms maintain the quiescent state of the HIV promoter [5–7]. Among the well-characterized factors that maintain latency are cellular histone deacetylases (HDACs) that deacetylate many cellular proteins, including histones. There are 4 classes of HDACs: class I includes HDACs 1, 2, 3 and 8; class IIa, HDACs 4, 5, 7 and 9; class IIb, HDACs 6 and 10; and class IV, HDAC 11 (class I is nuclear, and the others are cytoplasmic). The class III HDACs, sirtuins, are not regulators of HIV transcription and are not responsive to traditional inhibitors of HDAC activity [7, 8]. Multiple studies have shown that HDAC are recruited to the HIV promoter by transcription factor complexes and maintain the long terminal repeat in a transcriptionally silent state. HDACs 1, 2, and 3 mediate the repression of HIV transcription [9, 10]. When studied in cell line and primary cell models of HIV latency, HDAC inhibitors lead to acetylation of lysine residues on histone tails, an event associated with induction of transcription at the HIV promoter [11–13]. In a recent clinical trial, the administration of a single dose of the HDAC inhibitor vorinostat (VOR) to 8 participants receiving suppressive antiretroviral therapy resulted in an increase of HIV RNA within resting CD4+ T cells, demonstrating for the first time disruption of HIV latency in vivo [14]. In this study design the pharmacokinetic profile of VOR was measured after an initial 400-mg dose, several weeks before a second, isolated dose of VOR. After this later dose, HIV RNA induction was specifically demonstrated within pools of resting, not total, CD4+ T cells (hence the term rc-RNA). However, the ability of multiple doses of VOR to continuously disrupt HIV latency has not yet been clearly demonstrated. In this study, we sought to determine whether administration of multiple doses of VOR would result in repeated induction of rc-RNA, in association with repeated increases in cellular acetylation, and whether such repetitive induction of bursts of viral gene expression for the latent proviral would be associated with a concurrent depletion of resting CD4+ T-cell infection. |
| Databáze: | OpenAIRE |
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