Anti-CMV CD8+ T-cell epitope specificities and T-cell receptor repertoires in African study subjects

Thesis

This work focuses on chronic viral infection in populations in sub-Saharan Africa. Although some of these viruses are endemic, there is a paucity of data charac- terising the immune responses in the relevant populations affected. The primary focus of this thesis is cytomegalovirus (CMV). Almost 90% of children in Africa are infected by the age of 12 months. A strong virus-specific immune response controls but does not clear CMV infection, and CMV typically remains latent; how- ever, reactivation is possible, particularly in the context of HIV infection and other states of immunosuppression. The high-frequency, immunodominant CD8+ T-cell responses, the CMV epitopes targeted, and the T-cell receptor repertoires underly- ing these responses have not previously been well defined in African populations. Furthermore, it is not known how the T-cell repertoire changes over the course of infection in response to CMV. To gain a better understanding of these aspects of CMV infection and immunity, I defined the immunodominant CMV-specific CD8+ T-cell responses within a cohort of sub-Saharan African study subjects (Chapter 3). Using next-generation sequencing of the CMV-specific CD8+ T-cell receptor (TCR) repertoire, focusing on a single immunodominant HLA-B^*44:03-restricted response, I studied TCR repertoire bias (Chapter 4) and the changes in the TCR repertoire within children and adults followed longitudinally over 10 years (Chapter 5). Two other viruses, human Parvovirus 4 (PARV4) and Hepatitis B virus (HBV) are also endemic in these populations, may, like CMV, also be of particular signifi- cance in the setting of HIV co-infection, but are under-represented in the literature for Africa. I present data that I contributed to projects setting out to improve our understanding of the local epidemiology of these infections and to characterise relevant CD8+ T-cell responses (Chapter 6). Together, this work contributes to- wards a better understanding of immune responses that control chronic infections prevalent in African populations.

Authors: Malik, A

• DOI: 10.5287/ora-vebmrexxd
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford