Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

Sergey Iordanskiy, Rachel Van Duyne, Gavin C. Sampey, Caitlin M. Woodson, Kelsi Fry, Mohammed Saifuddin, Jia Guo, Yuntao Wu, Fabio Romerio, Fatah Kashanchi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalVirology
Volume485
DOIs
StatePublished - Nov 1 2015
Externally publishedYes

Keywords

  • Apoptosis
  • CD4+ T cells
  • HIV-1 latency
  • HIV-1 reactivation
  • Humanized mice
  • Irradiation
  • Monocytes
  • Transcription
  • X-ray

ASJC Scopus subject areas

  • Virology

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