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Title: The role of neutralizing antibodies in HIV-1 infection
Author: Bonsall, David George
ISNI:       0000 0004 2695 9375
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Human immunodeficiency virus type 1 is a major cause of morbidity and mortality worldwide and there is urgent demand for a protective vaccine. A major goal of vaccine development is the elicitation of antibodies capable of neutralizing diverse strains. In order to achieve this goal it is necessary to understand the dynamic relationship between neutralizing antibodies (NAbs) and HIV-1, in vivo. In humans, HIV-1 rapidly escapes from NAbs, confirming that humoral responses inhibit virus replication. However, neutralizing responses are commonly detected in viraemic patients and the clinical impact of NAbs on HIV-1 control is unclear. To investigate this further, viral load (VL) and NAb activity were assessed longitudinally in patients enrolled into a clinical trial of short-course antiretroviral therapy (ART), administered in early infection. The aims of this study were two-fold: i) to understand the importance of VL in the control of NAb responses and ii) to assess whether NAbs contribute to durable control of VL set-point. A high-throughput pseudovirus neutralization assay was developed, using automated counting procedures to quantify infected TZM-bl reporter cells. The assay was used to assess NAb responses with autologous viruses derived from 22 patients. Seven patients with low VL set-points (<104 RNA copies/ml) failed to develop neutralizing responses throughout the 48-144 week follow-up period. In contrast, the remaining patients developed progressively-increasing neutralizing plasma titres (IC50) that correlated with the extent and timing of VL rebound after cessation of ART. This suggests that the production of NAbs depends on the duration and extent of viraemia in early infection. Viral load was poorly predictive of neutralizing responses against heterologous isolates assayed in 38 patients, suggesting that other factors are important in the production of antibodies with cross-neutralizing activity. Depletion of specific immunological compartments can yield crucial information as to their functional importance in vivo. We took advantage of a unique opportunity to investigate the role of NAbs and the consequences of their depletion in an HIV-1 infected human. Three years after cessation of short-course ART, the patient was treated for pre-existing low-grade lymphoplasmacytic lymphoma by antibodymediated depletion of CD20+ B cells using rituximab. This treatment was followed by a 1.7 log10 rise in HIV-1 VL which spontaneously reversed. Autologous NAb responses decreased as viraemia flared, and recovered as VL was controlled. Antibodies were found to target the CD4 binding site (CD4bs), as shown by competitive-binding assays. Sequence analysis revealed diversification through generation of new variants as NAbs decreased, with subsequent selection of NAb-resistant mutants at sites consistent with the binding data. These data suggest that B cell function contributed to long-term control of VL in this individual and that NAbs may be more important in controlling HIV-1 infection than previously suspected.
Supervisor: McClure, Myra ; George, Andrew Sponsor: Medical Research Council ; Wellcome Trust ; NIHR Biomedical Research Centre
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral