Adaptive immune evasion in clinically latent HIV infection

• Main Author: Andrews, Sophie Marie
• Other Authors: Rowland-Jones, Sarah ; Dong, Tao
• Published: University of Oxford 2016
• Subjects: 616.97
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.722576

HIV is a master of immune evasion, utilising a range of different techniques to not only survive the human immune system, but also mediate its eventual catastrophic decline. Understanding how HIV evades the adaptive immune response is paramount to developing effective treatments and vaccines. This thesis aimed to investigate three key ways in which HIV-1 and HIV-2 mediate immune evasion in the context of clinically latent infection. Chapter three summarises a study into selection pressure and mutation in the gp120 envelope gene in a narrow-source HIV-1 cohort of former plasma donors (FPDs) from China. This study further characterised the cohort, and identified specific mutations in the gene consistent with antibody and CTL-driven selection pressure. Chapter four describes an investigation into the downregulation of HLA-I mediated by primary isolates of HIV-1 and HIV-2 Nef. Nef-mediated HLA-I downregulation contributes to the evasion of CTL responses. In stark contrast to previous reports, no evidence for differential downregulation of HLA-A and HLA-B was detected, but primary isolates invariably showed reduced activity relative to laboratory-adapted and consensus variants. In performing this study, a number of limitations came to light regarding how bifurcate analyses are used to interpret flow cytometric data collected in studies of receptor modulation. A novel technique - SWARM - was therefore developed to address these limitations, and is described in chapter five. Chapter six aimed to address why CTL responses against HIV-2 Nef are rare, despite HIV-1 Nef being highly immunogenic. A series of in vitro (immuno)proteasomal processing assays revealed HIV-2 Nef is more extensively digested than HIV-1 Nef, but further experimentation is required to explain the difference in response. Finally, chapter seven briefly summarises a successful collaborative attempt to resolve the first ever crystal structure of HIV-2 Nef.