The impact of neutralizing antibody and ADCC responses on HIV-1 envelope evolution in early infection
type: CreativeWork
description: The development of an effective HIV-1 vaccine remains a global priority. Neutralizing antibodies (nAbs), which block infection by cell-free virus, are likely to be an important response for vaccines to elicit. However, evidence from the RV144 vaccine trial and non-human primate vaccine studies suggest antibody-dependent cellular cytotoxicity (ADCC) responses, which target virus-infected cells, may also be protective. This thesis uses deep sequencing, together with immune assays, to characterise HIV-1 Envelope evolution associated with both nAb and ADCC responses in early infection, and investigates broadly neutralizing and non-neutralizing monoclonal antibody ADCC activity against subtype C viruses. Recent advances in deep sequencing approaches, coupled with the primer ID method which barcodes each viral genome, enabled us to generate thousands of viral sequences to accurately track viral population dynamics in early infection. In all participants investigated, there was a significant drop in the relative frequency of wildtype (WT) virus following nAb responses. However, in three of the seven participants, when controlling for changes in viral load (VL) over time, we observed that the WT load (frequency of the WT residue x total VL) remained relatively stable despite an effective nAb response. Instead, there was an outgrowth of the escaped virus with a concomitant increase in viral loads. We found that nAbs were inefficient at blocking cell-cell transmission of early WT and escape viruses, identifying this as one mechanism by which viruses may persist despite the presence of nAbs. These results suggest that other antibody effector functions such as ADCC, which target infected cells, may be important to elicit in a protective HIV-1 vaccines. If ADCC responses are important in controlling viral populations, one would expect to find evidence of viral escape from these responses. In all nine participants investigated, we found ADCC responses emerged prior to nAb respons…
abstract: The development of an effective HIV-1 vaccine remains a global priority. Neutralizing antibodies (nAbs), which block infection by cell-free virus, are likely to be an important response for vaccines to elicit. However, evidence from the RV144 vaccine trial and non-human primate vaccine studies suggest antibody-dependent cellular cytotoxicity (ADCC) responses, which target virus-infected cells, may also be protective. This thesis uses deep sequencing, together with immune assays, to characterise HIV-1 Envelope evolution associated with both nAb and ADCC responses in early infection, and investigates broadly neutralizing and non-neutralizing monoclonal antibody ADCC activity against subtype C viruses. Recent advances in deep sequencing approaches, coupled with the primer ID method which barcodes each viral genome, enabled us to generate thousands of viral sequences to accurately track viral population dynamics in early infection. In all participants investigated, there was a significant drop in the relative frequency of wildtype (WT) virus following nAb responses. However, in three of the seven participants, when controlling for changes in viral load (VL) over time, we observed that the WT load (frequency of the WT residue x total VL) remained relatively stable despite an effective nAb response. Instead, there was an outgrowth of the escaped virus with a concomitant increase in viral loads. We found that nAbs were inefficient at blocking cell-cell transmission of early WT and escape viruses, identifying this as one mechanism by which viruses may persist despite the presence of nAbs. These results suggest that other antibody effector functions such as ADCC, which target infected cells, may be important to elicit in a protective HIV-1 vaccines. If ADCC responses are important in controlling viral populations, one would expect to find evidence of viral escape from these responses. In all nine participants investigated, we found ADCC responses emerged prior to nAb respons…
author: Mielke, Dieter
language: eng
date published: 2017
date modified: 2026-07-22T22:23:19Z
provider: University of Cape Town
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Division of Virology

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11427/27280