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Title: Attenuation of macrophage IL-10 responses by HIV-1
Author: Stirling, David
ISNI:       0000 0004 7661 1246
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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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.
Supervisor: Noursadeghi, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available