Griffith, Sarah A;
(2023)
Investigating the humoral and B cell response during HIV infection to identify phenotypes associated with the development of HIV broadly neutralising antibodies.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Only 1-10% of HIV-1 infected individuals produce antibodies with broad neutralisation against heterologous viruses. These broadly neutralising antibodies (bnAbs) and their development are of interest due to in vivo studies showing that bnAbs can provide passive protection in animal models and delay viral rebound in humans. However, attempts to elicit bnAb responses during immunisation studies and vaccine trials have been largely unsuccessful. Therefore, there is a need to investigate host immune responses associated with HIV bnAb development. To address this, a cohort of treatment naïve HIV infected individuals were assessed for neutralisation breadth and identified the top neutraliser, T125. Fluorescence-activated cell sorting (FACS) using HIV envelope probes was performed to clone single B cells and isolate antibodies from T125. This produced monoclonal antibodies with different HIV neutralisation profiles, including a bnAb. The phenotype of B cells from two timepoints of this viraemic bnAb donor was also assessed during FACS and revealed that the tissue-like CD21-/CD27- B cell population was not enlarged, as canonically seen in HIV viraemia. A Smart-Seq2 single-cell RNA-sequencing pipeline was also established to investigate rare antigen-specific cell phenotypes. This yielded single-cell transcriptomes for HIV-specific IgG+ B cells from the bnAb donor which were compared to larger scRNA-seq datasets from HIV-infected donors and uninfected controls. This validated flow cytometry observations that the viraemic bnAb donor had a normalised B cell population, similar to uninfected controls. In addition, limited inflammatory stimulation was found in the memory B cells of uninfected controls, unlike viraemic donors. It was therefore proposed that preservation of memory B cell homeostasis and bnAb development, in the face of viraemia, was linked to IFN suppression. In support of this, plasma from top neutralisers in the cohort were capable of blocking type II IFN, which has previously been associated with the disruption of memory B cell subsets.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the humoral and B cell response during HIV infection to identify phenotypes associated with the development of HIV broadly neutralising antibodies |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10172130 |
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