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Title: HIV-1 induction of macrophage immune mediators
Author: Dacon, Cherrelle
ISNI:       0000 0004 8508 3406
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Clinical studies convincingly associate increased monocyte migration and markers of myeloid cell activation with the pathogenesis of inflammatory conditions in HIV-1-infected individuals. However, the mechanisms by which myeloid cells contribute to HIV-1-associated inflammation are poorly understood. HIV-1 infection of human macrophages is believed to induce an innate immune response that includes IFN-I production. Previous studies also implicate the HIV-1 accessory protein Vpr as a potential modulator of pro-inflammatory antiviral responses to HIV-1 infection, but these reports are contradictory and require clarification. To determine the immune mediators induced by HIV-1 and modulated by HIV-1 Vpr, I transduced human monocyte-derived macrophages with single-round pseudotyped viruses that were either competent or deleted for Vpr expression. Wide-scale soluble proteome analysis of conditioned media from the HIV-1-transduced human macrophages highlights that HIV-1 induces expression of a subset of pro-inflammatory factors, among which the interferon gamma-induced chemokine CXCL10/IP-10 is markedly enhanced. I find no evidence of enhanced primary monocyte migration towards either transduced MDM supernatants or recombinant soluble Env, a ligand for CCR5. Further analyses of macrophage supernatants using an IFN-reporter cell line and multiplex immunoassays show that HIV-1 Vpr expression downregulates IFN-α and IL-1β production. Together, these data support the idea MDMs elicit a modest innate response to HIV-1 of which the accessory protein Vpr is a negative regulator.
Supervisor: Sattentau, Quentin ; Russell, Rebecca Sponsor: Rhodes Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: HIV/AIDS ; Virology ; Immunology ; Inflammation