title: Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells.
abstract: The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4(+) T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4(+) T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4(+) T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the "Shock and Kill" strategy for latently HIV-1 infected cells.
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Iordanskiy
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Van Duyne
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Sampey
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Woodson
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Kelsi
authors.initials: K
authors.lastname: Fry
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Saifuddin
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Romerio
authors.affiliation: School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA. Electronic address: fkashanc@gmu.edu.
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects*; D054713:Bryostatins / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology / Q000528:radiation effects*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009000:Monocytes; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation / Q000528:radiation effects; D014779:Virus Replication / Q000528:radiation effects
chemical_list: D019380:Anti-HIV Agents; D054713:Bryostatins; D012367:RNA, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C046785:bryostatin 1; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D012319:RNA Polymerase II; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Apoptosis; CD4+ T cells; HIV-1 latency; HIV-1 reactivation; Humanized mice; Irradiation; Monocytes; Transcription; X-ray