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Attenuation of macrophage IL-10 responses by HIV-1

Stirling, David; (2019) Attenuation of macrophage IL-10 responses by HIV-1. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

HIV-1 infection of monocyte derived macrophages (MDM) attenuates innate immune IL-10 transcriptional responses, resulting in increased inflammation. I sought to identify the host and virus determinants of this effect to provide novel insights into HIV-associated immune dysfunction and the mechanisms that regulate IL-10 responses. I established a protocol in which THP-1 cells can be differentiated to a macrophage like phenotype able to generate innate immune IL-10 responses and confirmed that this was attenuated by HIV 1. I found that at least one of the HIV accessory genes vpr or vpu were necessary for IL-10 attenuation in THP-1s, but not in MDMs. I focussed my remaining experiments on MDMs in which I also introduced single cell analysis using RNA fluorescence in situ hybridisation. In this model, neither HIV 1 accessory proteins nor productive HIV 1 infection was necessary for attenuation of IL-10. Instead I found that HIV 1 RNA was necessary and sufficient for this phenotype. TLR8-binding HIV 1 RNA motifs and a synthetic TLR8 ligand recapitulated attenuation of macrophage IL-10 responses, implicating a role for TLR8. This interaction would be expected to lead to induction of type I interferons (IFN). Consistent with this, type I IFN attenuated IL-10 responses and its effect was reversed by blocking the type I IFN receptor. However, in the same model, HIV 1 did not induce IFN responses and HIV 1 attenuation of IL-10 was not reversed by IFN receptor blockade. In addition, transient exposure to HIV-1 achieved sustained attenuation of macrophage IL-10 responses. My data support a model in which incoming HIV-1 RNA interacts with TLR8, leading to specific transcriptional regulation of IL-10 independently of IFN induction, most likely via epigenetic mechanisms. These data reveal a novel pathway for adaptation of innate immune responses and a potential mechanism for immune activation in HIV-1 infection due to deficient IL-10 immunoregulation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Attenuation of macrophage IL-10 responses by HIV-1
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/ 4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: Virology, Immunology, Macrophage, HIV, Human Immunodeficiency Virus, Innate Immunity
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10069136
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