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Title: HIV-specific interleukin-10 responses and immune modulation
Author: Clutton, Genevieve Tyndale
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Interleukin-10 (IL-10) helps to limit the duration of potentially harmful inflammatory responses but has also been implicated in the persistence of a number of chronic viral infections. This thesis aimed to investigate the phenotype and function of HIV-specific IL-10-producing cells in chronic HIV-1 infection, and the effect of IL-10 blockade on responses to candidate HIV-1 vaccines. A cytokine capture assay was used to determine the HIV-specific cellular sources of IL- 10 in PBMC from 55 chronically infected individuals. A rare subset of CD8+ T cells was found to be the major HIV-1 Gag-specific IL-10-producing population; these cells were restricted to ART-naïve individuals and did not express the regulatory T cell markers CD25 or FoxP3 but could co-express IFN-γ. A proportion of the population (median 48% and 9% respectively) expressed the β7 chain of the gut-homing integrin α4β7 and the chemokine receptor CXCR3, which mediates lymphocyte migration to sites of inflammation. Experimental depletion of Gag-specific IL-10+ CD8+ T cells did not affect T cell activation, or the production of cytokines such as IL-2 or IFN-γ during short-term culture. However, depletion was associated with a significant increase in CD38 expression on CD14+ monocytes, a trend towards increased HLA-DR expression on the same cells, and a significant increase in the concentration of the pro-inflammatory cytokine IL-6 in culture supernatants. There was also a significant increase in the number of HIV-infected (p24 antigen+) CD4+ T cells in cultures depleted of Gag-specific IL-10+ CD8+ T cells after 3 days, indicating that this population may contribute to control of viral replication. In order to determine the effect of IL-10 blockade on vaccine immunogenicity, IL-10R blocking antibody was administered to BALB/c mice prior to immunisation with two HIV-1 candidate vaccines, HIVA and HIVconsv. IL-10R blockade resulted in a trend towards increased IFN-γ production by CD8+ T cells in response to the dominant H (Env) and P (Pol) epitopes of HIVA, and a significant increase in IFN-γ ELISPOT responses to the subdominant G1 (Gag) epitope of HIVconsv in vitro. Collectively, these data suggest that IL-10-producing cell populations may play critical but different roles in chronic infection and vaccination. Further research into how the timing of IL-10 responses affects disease outcome may allow IL-10 blockade to be explored as a therapeutic strategy in humans.
Supervisor: Dorrell, Lucy Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Infectious diseases ; Immunology ; HIV/AIDS ; Medical Sciences ; Vaccinology