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Title: HIV-1 neutralisation and other aspects of the envelope glycoprotein
Author: Lai, Pei-Jen
ISNI:       0000 0004 2687 3221
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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The absence of an effective humoral response contributes to the failure of controlling HIV-1 infection. Methods to elicit a potent neutralising antibody response is still underway and this thesis explores three aspects that can affect neutralisation. The pseudovirus-based assay is now recommended as the standard assay for assessing neutralising antibody response. However, recent studies have reported discrepancies between pseduovirus-based assay and conventional PBMCs or other cell-based assays. The first aim is to investigate possible causes behind this difference. The effect of virus producer cell type and virus platform (pseudovirus vs. replication-competent) was examined and both parameters can affect neutralisation. The second aim was to study the the neutralising antibody response in patients with primary HIV-1 infection. A panel of 6 patients were selected from the SPARTAC clinical trial. Pseudoviruses were constructed with the env gene derived from patient samples at week 0 (baseline) and week 52. The evolutionary history and the neutralisation sensitivity of these primary isolates against a panel of broadly neutralising antibodies and heterologous and autologous sera were studied. The week 52 isolates escaped from antisera neutralisation rapidly, most likely at the glycan level. In addition, viral load was found to correlate directly with intra-patient viral diversity and evolutionary divergence over time. Finally, the effect of Nef on HIV-1 neutralisation was investigated. Recent reports suggest that Nef modifies HIV-1 envelope glycoprotein. Hence, neutralising antibody response might also be modified in the absence of Nef. When subjected to neutralisation with a panel of monoclonal antibodies, the Nef-deleted (ΔNef) HIV-1 was more readily neutralised than the wild-type (WT) virus. Immunoprecipitation assays showed that neutralising antibodies can capture ΔNef virus more efficiently than WT virus. However, the enhanced neutralisation of ΔNef virus was neither due to CD4-down regulation nor difference in glycosylation.
Supervisor: Jeffs, Simon ; McClure, Myra Sponsor: Overseas Research Students Awards Scheme ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral