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Viral protein R of HIV type‐1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway
Author(s) -
Doi Akihiro,
Iijima Kenta,
Kano Shigeyuki,
Ishizaka Yukihito
Publication year - 2015
Publication title -
microbiology and immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.664
H-Index - 70
eISSN - 1348-0421
pISSN - 0385-5600
DOI - 10.1111/1348-0421.12266
Subject(s) - biology , stat protein , transcription (linguistics) , activator (genetics) , microbiology and biotechnology , retrotransposon , signal transduction , glutamate receptor , human immunodeficiency virus (hiv) , virology , stat3 , gene , genetics , transposable element , receptor , genome , linguistics , philosophy
Viral protein R (Vpr) of HIV‐1 plays an important role in viral replication in macrophages. Various lines of evidence suggest that expression of Vpr in macrophages causes immunopathogenesis; however, the underlying mechanism is not yet fully understood. In this study, it was shown that recombinant Vpr (rVpr) induces retrotransposition of long interspersed element‐1 in RAW264.7, a macrophage‐like cell line, and activates reverse transcriptase‐dependent immunotoxic cascades including production of IFN‐β and phosphorylation of signal transducer and activator of transcription 1 (STAT1). Knockout experiments based on the CRISPR/Cas9 nickase system further demonstrated that cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS) and stimulator of interferon gene (STING) are responsible for IFN‐β production and STAT1 phosphorylation, respectively. Moreover, rVpr was found to increase production of glutaminase C, a regulator of glutamate synthesis, which is also dependent on the cGAS−STING pathway. Taken together with reports that glutaminase C is involved in the pathogenesis of HIV‐associated neurocognitive disorder (HAND) and that Vpr is detectable in the cerebrospinal fluid of HIV‐1‐positive patients, a possible role of Vpr‐induced L1‐RTP and immunotoxic cascades in the development of HAND is discussed.