Around 35 million people are living with HIV-1 infection globally. Untreated infection results in progression to AIDS and mortality. Current antiretroviral treatment is not curative and does not treat the underlying inflammatory processes caused by the presence of HIV-1, a cytotoxic and tissue toxic virus. HIV-1 triggers overwhelming and dysregulated pro-inflammatory cytokine response during infection, including deranged interleukin-1 beta and interleukin-18 levels. We investigate the mechanisms underlying how HIV-1 activates the inflammasome, a multimolecular complex involved in the production of potent inflammatory markers such as interleukin-1 beta and interleukin-18. The inflammasome is often activated in a two-signal process requiring initial sensing by Toll-like receptors to generate signal 1, priming inflammasome components; and signal 2 sensed by NOD-like receptors which recruit and activate the inflammasome. Human leukocytes were stimulated with live HIV-1 or its cognate envelope proteins gp120 or gp41, or transfected with plasmids encoding HIV-1 viroporin Vpu or gp41. NLRP3 knock-down attenuated inflammasome activation and interleukin-1beta/interleukin-18 secretion following HIV-1, gp120 or gp41 stimulation. gp120 induced inflammasome activation also required the presence of TLR2 and TLR4, suggesting a degree of cooperation in effecting signal 1. Dual NLRP3/NLRC4 knockdown reduced the inflammasome response to HIV-1 gp41 stimulation which was found to be dependent on chloride anion flux across integral lipid rafts in the trans-Golgi network. The results imply a critical role for TLR2 and TLR4 in recognising HIV-1 proteins providing signal 1 for inflammasome formation. Ion fluxes in the cell due to HIV-1 infection are the catalyst that triggers inflammasome activation via NLRP3 or NLRC4, and secretion of interleukin-1 beta and interleukin-18. The findings contribute to the general understanding of HIV-1 recognition by the human innate immune system and help to further clarify precisely how HIV-1 causes striking dysregulation in cytokine profiles in people living with HIV-1 infection.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:723605 |
| Date | January 2017 |
| Creators | Ward, Christopher |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/104950/ |
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