Collier, Oluwadamilola Aderonke; (2022) Within-host evolution and virus escape of two important pandemic viruses. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Viruses are known to adapt to the constraints of the niche in which they find themselves. This leads to within-host adaptations, detected as nucleic acid base mutations, protein changes or epigenetic modification. These changes are driven by selection pressures which may be due to immune responses to the virus, drug treatment and requirement to exist in specific compartments within the host. Cerebrospinal fluid (CSF) escape and central nervous system (CNS) compartmentalisation are problems in HIV-1 that are not fully understood and have implications for HIV-1 treatment and cure. The true extent of this problem in subtype C HIV-1, which is responsible for the epidemic in Southern Africa is unknown. The prevalence of these were determined in a cohort of participants co-infected with HIV-1 and cryptococcal meningitis. Following this, the phenotypic characteristics of CSF and plasma derived clones that may underly the mechanisms by which they adapt to the CNS were investigated. CSF escape was uncommon in this cross sectional study. Four participants underwent in-depth characterisation of the genomes in both the CSF and plasma. This revealed that 2 out of 4 of them had CNS compartmentalisation according to analyses of their phylogeny. The diversity of the CSF and plasma env genomes were different in these individuals and are most likely reflective of their unique within-host selection pressures. All clones tested utilised the CCR5 co-receptor for viral entry with some evidence that CSF derived clones may have a higher affinity for the CCR5 coreceptor and hence better adapted to infect CNS macrophage with low levels of CD4. An in-depth analysis of within-host evolution of SARS-CoV-2 in a chronic infection case was undertaken. Escape mutations were identified and their functional relevance were tested in infection and neutralisation experiments. Additionally, factors related to poor immune response to mRNA BNT162b2 SARS-CoV-2 vaccine were investigated. The findings revealed a dynamic shift in viral population in vivo that was likely driven by pressure from treatment with remdesivir and convalescent plasma. In vitro testing of emerging Spike mutants revealed that D796H mutation facilitated escape from neutralising antibodies but was accompanied by a reduction in infectivity. Meanwhile, △H69/V70 deletions had no impact on the neutralisation activity of convalescent plasma but increased the infectivity of the pseudotyped virus. Importantly older age i.e ≥80 years was a risk factor for lower Spike-specific antibody binding levels, lower neutralisation responses against Spike pseudotyped viruses and lower T cell interferon gamma (IFN) and IL-12 responses following the first dose of mRNA BNT162b2 vaccine. However, these poor responses were overcome by the second dose in all participants tested. These findings will contribute to our understanding of within-host viral evolution and have implications for patients care, vaccine and cure strategies.

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