HLA-I, Natural Killer Cells and T Lymphocytes in Paediatric HIV Functional Cure

Thesis

Achieving a functional cure for HIV-1 remains one of the greatest challenges in medicine. Post-treatment control (PTC), where individuals sustain virological suppression after discontinuing antiretroviral therapy (ART), represents a particularly promising strategy. Infants appear to have enhanced PTC potential due to early ART initiation, immune tolerance, and the infection of less fit viruses compared to adults, making this group particularly informative for studying mechanisms of PTC. This thesis investigates the immunogenetic and immunological determinants of PTC in early ART-treated children living with HIV, to inform cure-directed interventions and identify paediatric candidates for analytical treatment interruption (ATI) trials. Chapter 3 reveals that children carrying low-expression HLA-A alleles exhibit reduced HIV-1 DNA levels, suggesting smaller reservoirs and enhanced cure potential, which were linked with NK cell phenotype and function. In contrast, females with protective HLA-B alleles displayed larger reservoirs associated with Th17-skewed immune profiles and therefore reduced cure potential. Chapter 4 demonstrates the potential for HIV-1 to alter population-level HLA-I frequencies in KwaZulu-Natal and that the introduction of ART has halted this selective pressure. Additionally, infants born in the ART era were shown to have reduced frequencies of high-expression HLA-A alleles compared to the pre-ART era, favouring PTC. Chapter 5 explores immunological differences between HLA-B*58:01 and HLA-B*58:02. HLA-B*58:01 was linked to heightened immune activation relative to HLA-B*58:02 in both healthy adults and early-ART treated children, suggesting that, despite its ‘protective’ classification in ART-naïve settings, HLA-B*58:01 may be less compatible with functional cure in early ART-treated children compared to HLA-B*58:02. Together, these findings highlight factors that enhance paediatric functional cure, including low HLA-A expression, heightened NK cell functionality, ‘disease-susceptible’ HLA-B alleles, and high ART coverage. This work helps advance our understanding of factors that enhance paediatric HIV-1 functional cure and supports the long-term vision of relieving children of lifelong ART.

Authors: Herbert, N

• DOI: 10.5287/ora-00a9nxje0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: paediatrics; HIV-1; immunology
• Subjects: Clinical immunology; HIV-positive children; Evolution