Gkouleli, Triantafylia Maria; (2023) Investigation of Immunological and Virological Markers in HIV Perinatally Infected Children. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Recent years have seen tremendous progress in HIV prevention methods and an impressive 70% decline in newly acquired paediatric infections. However, even at approximately 30%, the rate of new infections remains unacceptably high. Additionally, an increasing number of perinatally HIV-1 infected children are reaching adolescence and adulthood. Despite the significant patient care challenges that will unavoidably arise due to viral persistence, in cases suboptimal ART adherence, and the lack of a cure, this important cohort remains understudied. There is still important work to be done to ensure optimal treatment management and best quality of life in the years to come, by better understanding their viral and immunological dynamics. This thesis aims to investigate immunological and virological markers by using three distinct paediatric HIV-1 cohorts. A cohort of early-treated, well-suppressed, perinatally infected children and adolescents, part of the CARMA study, is used to study virological and immunological characteristics. The size and composition of their HIV-1 reservoir is evaluated by developing a RT-qPCR assay to examine the presence of cell-associated HIV-1 RNA. Immunological characteristics, such as the TCR repertoire diversity, clonotype sharing, antigen “specificity”, and the presence of invariant MAIT cells are studied by using a next generation sequencing method. Late-treated children, part of the LD study, and children that underwent planned treatment interruption, part of the PENTA11 study, are selected to study the immunological effects of deferred or well-monitored interrupted treatment. Despite limitations and restrictions arising from studying small numbers of paediatric patients, the work here highlights the benefits and importance of early ART initiation and patient monitoring. Younger age at treatment initiation appears to have a beneficial effect in reducing the size of the viral reservoir, however HIV-1 CA-RNA is still detectable in 65% of the CARMA study participants. The greater thymic function capability of children, younger age at ART initiation and uninterrupted treatment and the presence of invariant immune cells, can provide an immunological advantage, with a higher repertoire diversity, great capacity for antigen recognition and immune response. This work demonstrates that future longitudinal studies, that include larger international cohorts of HIV-1 perinatally infected children and adolescents, as well as age-matched healthy controls, will be necessary to determine the factors that affect the immunological and virological parameters in well-suppressed individuals, such as chronic immune activation and dysregulation, and HIV-1 reservoir replenishment. By continuously studying and elucidating their virological and immunological profiles, and by having an array of markers to follow, we will be able to predict therapy responses and inform novel treatment strategies.

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