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Macrophage activation of cGAS and TRIM5 distinguish pandemic and non-pandemic HIV

View ORCID ProfileLorena Zuliani Alvarez, Morten L. Govasli, Jane Rasaiyaah, Chris Monit, Stephen O. Perry, Rebecca P. Sumner, Simon McAlpine-Scott, Claire Dickson, K. M. Rifat Faysal, Laura Hilditch, Richard J. Miles, Frederic Bibollet-Ruche, Beatrice H. Hahn, View ORCID ProfileTill Boecking, Nikos Pinotsis, Leo C. James, David A. Jacques, Greg J. Towers
doi: https://doi.org/10.1101/2022.01.21.477263
Lorena Zuliani Alvarez
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
2Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
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  • ORCID record for Lorena Zuliani Alvarez
Morten L. Govasli
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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Jane Rasaiyaah
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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Chris Monit
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
3Carnall Farrar, 1 Lyric Square, Hammersmith, London, W6 0NB UK
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Stephen O. Perry
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
4Quell Therapeutics Ltd, Translation & Innovation Hub, 84 Wood Lane, W12 0BZ
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Rebecca P. Sumner
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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Simon McAlpine-Scott
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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Claire Dickson
5EMBL Australia Node in Single Molecule Science, School of Medical Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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K. M. Rifat Faysal
5EMBL Australia Node in Single Molecule Science, School of Medical Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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Laura Hilditch
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
6Nucleus Global, 76-78 Old Street, London, EC1V 9AZ
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Richard J. Miles
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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Frederic Bibollet-Ruche
7Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
8Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Beatrice H. Hahn
7Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
8Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Till Boecking
5EMBL Australia Node in Single Molecule Science, School of Medical Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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Nikos Pinotsis
9Institute of Structural and Molecular Biology, Birkbeck College, London, WC1E 7HX, UK
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Leo C. James
10MRC Laboratory of Molecular Biology, Cambridge, UK
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David A. Jacques
5EMBL Australia Node in Single Molecule Science, School of Medical Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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  • For correspondence: g.towers@ucl.ac.uk
Greg J. Towers
1Division of Infection and Immunity, UCL, Gower Street, London, WC1E 6BT, UK
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  • For correspondence: g.towers@ucl.ac.uk
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SUMMARY

Pandemic viruses remain a global threat to health and economics but how they adapt to become pandemic remains poorly understood. Here we compare pandemic HIV-1(M) and non-pandemic HIV-(O) and HIV-2 strains finding that non-pandemic HIV replicate poorly in myeloid cell models due to activation of cGAS and TRIM5, and ensuing antiviral responses. We use phylogenetics and viral capsid structural biology to define specific differences between pandemic and non-pandemic HIV capsids and demonstrate that their genetic reversal in HIV-1(M) mutants causes TRIM5, cGAS and innate immune activation. We propose a model in which the parental lineage of pandemic HIV-1(M) has uniquely evolved a dynamic capsid that avoids activation of cGAS and TRIM5 to establish cloaked replication in myeloid cells. The unique adaptations of the pandemic virus lineage suggests a role in effective human-to-human transmissibility and highlight the importance of avoiding innate immune activation during pandemic human-to-human viral transmission.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 22, 2022.
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Macrophage activation of cGAS and TRIM5 distinguish pandemic and non-pandemic HIV
Lorena Zuliani Alvarez, Morten L. Govasli, Jane Rasaiyaah, Chris Monit, Stephen O. Perry, Rebecca P. Sumner, Simon McAlpine-Scott, Claire Dickson, K. M. Rifat Faysal, Laura Hilditch, Richard J. Miles, Frederic Bibollet-Ruche, Beatrice H. Hahn, Till Boecking, Nikos Pinotsis, Leo C. James, David A. Jacques, Greg J. Towers
bioRxiv 2022.01.21.477263; doi: https://doi.org/10.1101/2022.01.21.477263
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Macrophage activation of cGAS and TRIM5 distinguish pandemic and non-pandemic HIV
Lorena Zuliani Alvarez, Morten L. Govasli, Jane Rasaiyaah, Chris Monit, Stephen O. Perry, Rebecca P. Sumner, Simon McAlpine-Scott, Claire Dickson, K. M. Rifat Faysal, Laura Hilditch, Richard J. Miles, Frederic Bibollet-Ruche, Beatrice H. Hahn, Till Boecking, Nikos Pinotsis, Leo C. James, David A. Jacques, Greg J. Towers
bioRxiv 2022.01.21.477263; doi: https://doi.org/10.1101/2022.01.21.477263

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