title: Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway.
abstract: 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.
authors.affiliation: Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-0052.|Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba, 305-0006.|Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo, 102-0083.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Doi
authors.affiliation: Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-0052.
authors.forename: Kenta
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba, 305-0006.|Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-0052, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kano
authors.affiliation: Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-0052.
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
mesh_terms: D000818:Animals; D005971:Glutamates / Q000096:biosynthesis*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D000067996:RAW 264.7 Cells; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D005971:Glutamates; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D050794:STAT1 Transcription Factor; D054325:vpr Gene Products, Human Immunodeficiency Virus; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: glutamate; retrotransposition; signal transducer and activator of transcription 1; viral protein R