HIV-1 Vpr antagonizes cGAS sensing by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Khan, H.; Sumner, R. P.; Rasaiyaah, J.; Tan, C. P.; Rodriguez-Plata, M. T.; Van Tulleken, C.; Fink, D.; Zuliani-Alvarez, L.; Thorne, L.; Stirling, D.; Towers, G. J.

doi:10.1101/2020.02.22.960757

bioRxiv · 10.1101/2020.02.22.960757

HIV-1 Vpr antagonizes cGAS sensing by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport

Khan, H.·Sumner, R. P.·Rasaiyaah, J.·Tan, C. P.·Rodriguez-Plata, M. T.·Van Tulleken, C.·Fink, D.·Zuliani-Alvarez, L.·Thorne, L.·Stirling, D.·Towers, G. J.

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Abstract

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Khan, H., Sumner, R. P., Rasaiyaah, J., Tan, C. P., Rodriguez-Plata, M. T., Van Tulleken, C., Fink, D., Zuliani-Alvarez, L., Thorne, L., Stirling, D., Towers, G. J.. 2020-02-24. HIV-1 Vpr antagonizes cGAS sensing by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport. https://doi.org/10.1101/2020.02.22.960757

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