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Early innate immune responses in HIV infection

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Title: Early innate immune responses in HIV infection
Authors: Skelton, Jessica Katy
Item Type: Thesis or dissertation
Abstract: Human immunodeficiency virus (HIV)-1 has evolved to evade many cellular innate immune pathways and yet is most typically associated with aberrant immune activation. However, most current models have evaluated this during chronic phases of HIV-1 infection and to date, the early innate immune kinetics remain elusive. Here, we evaluate the impact of HIV-1 infection on cell-intrinsic innate immune responses using both IFN reporter cell lines and primary cells in vitro, as well as in vivo in humanized mice. We delineate the immune activation during the HIV-1 eclipse, burst and chronic phases of infection in humanized mice. We show that HIV-1 actively down-regulates type I interferon (IFN) and interferon-stimulated gene (ISG) responses in peripheral, but not splenic cells during the eclipse phase of infection. Using a combination of phosflow, flow cytometry and gene expression analysis we define the ability of HIV-1 to differentially affect its innate immune recognition in peripheral and lymphoid cells during the burst phase of infection. Contrastingly, during chronic HIV-1 infection, we identified a targeted down-regulation of HIV-1 restriction factor transcripts in peripheral circulation, which is not mirrored in lymphoid tissues. Finally, using both small molecule inhibitors and previously described HIV-1 capsid mutant viruses, we evaluate the importance of HIV-1 capsid-co-factor interactions and demonstrate their importance in maintaining viral fitness and replication in vivo. Overall, our data suggest that nucleoporin-358, rather than cyclophilin A is responsible for the down-regulation of cell-intrinsic immune responses observed during HIV-1 infection. We highlight the importance of HIV-1 manipulation of host innate immune responses to propagate infection at different stages, further emphasising the complexity of HIV-1 innate immune regulation. Taken together, we emphasise the need for consideration of compartmentalised responses when developing novel treatment strategies exploiting immune activation.
Content Version: Open Access
Issue Date: Feb-2019
Date Awarded: Jun-2019
URI: http://hdl.handle.net/10044/1/80049
DOI: https://doi.org/10.25560/80049
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Shattock, Robin
Ortega Prieto, Ana Maria
Sponsor/Funder: Imperial College London
Wellcome Trust (London, England)
European Union
Funder's Grant Number: 104771/Z/14/Z
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses