期刊
AIDS
卷 30, 期 13, 页码 2043-2052出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000001159
关键词
Crocodylus porosus; extracellular histones; histones; HIV-1 inhibition; innate immunity; neutrophil extracellular traps; saltwater crocodile
资金
- Canadian Foundation for AIDS Research (CANFAR)
- Ontario HIV Treatment Network (OHTN)
- Canadian Institutes for Health Research (CIHR)
- Centre for Innovation of Canadian Blood Services by Health Canada, a department of the federal government of Canada
Objective: It has been reported that crocodile blood contains potent antibacterial and antiviral properties. However, its effects on HIV-1 infection remain unknown. Design: We obtained blood from saltwater crocodiles to examine whether serum or plasma could inhibit HIV-1 infection. We purified plasma fractions then used liquid chromatography-mass spectrometry to identify the inhibitory protein factor(s). We then analyzed the ability of recombinant proteins to recapitulate HIV-1 inhibition and determine their mechanism of action. Methods: Crocodylus porosus plasma was tested for inhibition of Jurkat T-cell HIV-1 infection. Inhibitor(s) were purified by reverse-phase chromatography then identified by protein liquid chromatography-mass spectrometry. Anti-HIV-1 activity of purified plasma or recombinant proteins were measured by p24 enzyme-linked immunosorbent assay and luciferase readouts, and mechanism of action was determined by measuring HIV-1 RNA, cDNA and transcription (using 1G5 cells). Results: Crocodile plasma contains potent inhibitors of HIV-1(IIIB) infection, which were identified as histones. Recombinant human histones H1 and H2A significantly reduced HIV-1(JR-FL) infection (IC50 of 0.79 and 0.45 mu mol/l, respectively), whereas H4 enhanced JR-FL luciferase activity. The inhibitory effects of crocodile plasma, recombinant H1 or recombinant H2A on HIV-1 infection were during or post-viral transcription. Conclusion: Circulating histones in crocodile blood, possibly released by neutrophil extracellular traps, are significant inhibitors of HIV-1 infection in-vitro. Extracellular recombinant histones have different effects on HIV-1 transcription and protein expression and are downregulated in HIV-1 patients. Circulating histones may be a novel resistance factor during HIV-1 infection, and peptide versions should be explored as future HIV-1 therapeutics that modulate viral transcription. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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