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HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

View ORCID ProfileAnn-Kathrin Reuschl, View ORCID ProfileMaitreyi Shivkumar, Dejan Mesner, Laura J. Pallett, View ORCID ProfileJosé Afonso Guerra-Assunção, View ORCID ProfileRajhmun Madansein, View ORCID ProfileKaylesh J Dullabh, View ORCID ProfileAlex Sigal, View ORCID ProfileJohn P. Thornhill, Carolina Herrera, View ORCID ProfileSarah Fidler, View ORCID ProfileMahdad Noursadeghi, View ORCID ProfileMala K. Maini, View ORCID ProfileClare Jolly
doi: https://doi.org/10.1101/2021.01.25.428084
Ann-Kathrin Reuschl
1Division of Infection and Immunity, University College London, London, UK
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Maitreyi Shivkumar
1Division of Infection and Immunity, University College London, London, UK
2Present address: Leicester School of Pharmacy, De Montfort University, Leicester, UK
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Dejan Mesner
1Division of Infection and Immunity, University College London, London, UK
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Laura J. Pallett
1Division of Infection and Immunity, University College London, London, UK
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José Afonso Guerra-Assunção
1Division of Infection and Immunity, University College London, London, UK
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Rajhmun Madansein
3Department of Cardiothoracic Surgery, University of KwaZulu-Natal, Durban, South Africa
4Centre for the AIDS Programme of Research in South Africa, Durban, South Africa
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Kaylesh J Dullabh
3Department of Cardiothoracic Surgery, University of KwaZulu-Natal, Durban, South Africa
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Alex Sigal
5Africa Health Research Institute, Durban, South Africa
6School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
7Max Planck Institute for Infection Biology, Berlin, Germany
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John P. Thornhill
8Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
9Department of Infectious Diseases, Faculty of Medicine, Imperial College, London, UK
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Carolina Herrera
9Department of Infectious Diseases, Faculty of Medicine, Imperial College, London, UK
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Sarah Fidler
9Department of Infectious Diseases, Faculty of Medicine, Imperial College, London, UK
10Imperial College NIHR Biomedical Research Centre, London, UK
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Mahdad Noursadeghi
1Division of Infection and Immunity, University College London, London, UK
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Mala K. Maini
1Division of Infection and Immunity, University College London, London, UK
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Clare Jolly
1Division of Infection and Immunity, University College London, London, UK
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  • For correspondence: c.jolly@ucl.ac.uk
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Abstract

Human immunodeficiency virus type 1 (HIV-1) replicates in CD4+ T cells leading to profound T cell loss, immunological dysfunction and AIDS. Determining how HIV-1 shapes the immunological niche in which it resides to create a permissive environment is central to informing efforts to limit pathogenesis, disturb viral reservoirs and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate CD4+ T cells in vitro in order to make them permissive to infection. This dramatically alters T cell biology, obscuring native virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient and productive infection of resting CD4+ T cells without the need for prior activation. Infection is preferential for resting memory T cells, is observed with both CXCR4-tropic virus and CCR5-tropic transmitter-founder viruses and results in virus production and onward spreading infection. Strikingly, we find that HIV-1 infection of resting memory CD4+ T cells primes for induction of a tissue-resident memory (TRM)-like phenotype evidenced by upregulation of TRM markers CD69/CXCR6 alongside co-expression of CD49a, PD-1, CD101 as well as transcription factor Blimp-1. Furthermore, we reveal that HIV-1 initiates a transcriptional program that overlaps with the core TRM transcriptional signature. This reprograming depends on the HIV-1 accessory protein Vpr. We propose that HIV-1 infection drives a CD4+ TRM-phenotype potentially sequestering infected cells within tissues to support viral replication and persistence.

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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 25, 2021.
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HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells
Ann-Kathrin Reuschl, Maitreyi Shivkumar, Dejan Mesner, Laura J. Pallett, José Afonso Guerra-Assunção, Rajhmun Madansein, Kaylesh J Dullabh, Alex Sigal, John P. Thornhill, Carolina Herrera, Sarah Fidler, Mahdad Noursadeghi, Mala K. Maini, Clare Jolly
bioRxiv 2021.01.25.428084; doi: https://doi.org/10.1101/2021.01.25.428084
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HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells
Ann-Kathrin Reuschl, Maitreyi Shivkumar, Dejan Mesner, Laura J. Pallett, José Afonso Guerra-Assunção, Rajhmun Madansein, Kaylesh J Dullabh, Alex Sigal, John P. Thornhill, Carolina Herrera, Sarah Fidler, Mahdad Noursadeghi, Mala K. Maini, Clare Jolly
bioRxiv 2021.01.25.428084; doi: https://doi.org/10.1101/2021.01.25.428084

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