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Title: Modulation of cell-mediated immunity by HIV-1 infection of macrophages
Author: Bell, L. C. K.
ISNI:       0000 0004 5365 6097
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Cell-mediated immunity (CMI) is central to the host response to intracellular pathogens such as Mycobacterium tuberculosis (Mtb). The function of CMI can be modulated by human immunodeficiency virus (HIV)-1 via its pleiotropic effects on the immune response, including modulation of macrophages, which are parasitized by both HIV-1 and Mtb. HIV-1 infection is associated with increased risk of tuberculosis (TB), and so in this thesis I sought to explore the host/pathogen interactions through which HIV-1 dysregulates CMI, and thus changes the natural history of TB. Using an in vitro model of human monocyte-derived macrophages (MDMs), I characterise a phenotype wherein HIV-1 specifically attenuates production of the immunoregulatory cytokine interleukin (IL)-10 in response to Mtb and other innate immune stimuli. I show that this phenotype requires HIV-1 integration and gene expression, and may result from a function of the HIV-1 accessory proteins. I identify that the phosphoinositide 3-kinase (PI3K) pathway specifically regulates IL-10 production in human MDMs, and thus may be a target for HIV-1 to mediate IL-10 attenuation. I show that HIV-1 may attenuate IL-10 to maximise its own replication, and identify potential consequences of IL-10 attenuation for CMI. By using the tuberculin skin test (TST) as a human challenge model, I evaluate HIV-1 modulation of CMI in vivo in active TB patients, and demonstrate IL-10 attenuation in this context. I identify a role for type I inteferons (IFNs) in HIV-1 anergy, and observe exaggerated T helper 2 responses associated with the immune reconstitution inflammatory syndrome (IRIS). To fully explore CMI in vivo by transcriptional profiling, I utilize the transcriptional heterogeneity of stimulated macrophages to develop a modular analysis strategy for transcriptional profiles, and apply this in the TST model. My results delineate novel modulatory effects of HIV-1 on the function of CMI, and thus provide insights into immunopathogenesis in HIV-1/TB co-infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available