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Extracellular histones identified in crocodile blood inhibit in-vitro HIV-1 infection.

Extracellular histones identified in crocodile blood inhibit in-vitro HIV-1 infection.
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Kozlowski HN, Lai ET, Havugimana PC, White C, Emili A, Sakac D, Binnington B, Neschadim A, McCarthy SD, Branch DR,


Kozlowski HN, Lai ET, Havugimana PC, White C, Emili A, Sakac D, Binnington B, Neschadim A, McCarthy SD, Branch DR, (click to view)

Kozlowski HN, Lai ET, Havugimana PC, White C, Emili A, Sakac D, Binnington B, Neschadim A, McCarthy SD, Branch DR,

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AIDS (London, England) 30(13) 2043-52 doi 10.1097/QAD.0000000000001159

Abstract
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-1IIIB infection, which were identified as histones. Recombinant human histones H1 and H2A significantly reduced HIV-1JR-FL infection (IC50 of 0.79 and 0.45 μmol/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.

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