Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498361
Title: Antibody-dependent enhancement of HIV-1 infection
Author: Willey, Suzanne
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Abstract:
Antibody-dependent enhancement (ADE) is the process by which virus-specific antibodies enhance entry or replication of a virus, leading to increased infection and the potential to exacerbate disease progression or severity. In terms of HIV infection, ADE could make the difference between an ineffective vaccine and a dangerous one. There is also the possibility that ADE affects disease progression in natural infection. Here, one aspect of ADE, complement-mediated ADE (C'-ADE), was investigated in detail. An assay was developed to study C'-ADE in both R5- and X4-tropic HIV-1 strains in the context of early, primary infection and vaccination. A CD4+ T cell line was used for these studies which expressed the complement receptor 2 (CR2) and HIV-1 co-receptors CXCR4 and CCR5. C'-ADE in primary infection was investigated using serum samples collected longitudinally from infected individuals from as early as 12 days post onset of primary symptoms. When tested against autologous viruses isolated early after infection, C'-ADE was detected in 9 out of 10 patients. In some cases this was potent enough to produce increases in infection greater than 100-fold. Later virus isolates that evolved to escape antibody neutralisation were enhanced by sera that neutralised early virus. Competition studies carried out with neutralising and enhancing IgG showed neutralisation to be the dominant activity. Enhancing, but not neutralising, activity of patient sera was detected against heterologous primary isolates. Post-vaccination C'-ADE was investigated using sera from volunteers vaccinated with a monomeric gpl20 vaccine from a dual-tropic HIV-1 strain. Sera from vaccinees enhanced infection of the vaccine virus strain but did not neutralise it. Neutralisation was seen for an X4 virus strain, MN, and individuals that produced the most potent neutralisation against MN also produced the most potent enhancement of the vaccine strain. CR2-mediated increased attachment of opsonised viruses to the target cell was shown to be the principle mechanism of C'-ADE. The use of a CR2 cytoplasmic tail mutant showed that receptor signalling was not necessary for C'-ADE. Results from these studies show that antibodies that appear to be non-neutralising in neutralisation assay systems can actually have dramatic effects on virus infection in a different context. These new findings are considered in relation to existing knowledge on neutralisation and ADE of HIV.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.498361  DOI: Not available
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