HIV-related immune activation and clinical outcomes of mothers and infants in rural Zimbabwe

The increasing availability of antiretroviral therapy in sub-Saharan Africa has improved outcomes of pregnant women living with HIV and reduced vertical HIV transmission to children. However, the impact of maternal HIV on overall outcomes of children in the current antiretroviral therapy era remains uncertain. The research presented in this thesis was undertaken as part of the SHINE trial at the Zvitambo Institute for Maternal and Child Health Research in Zimbabwe, and has five broad findings. First, in the context of 80% antiretroviral coverage, children born to mothers with HIV had 41% higher mortality compared to children born to mothers without HIV. Second, HIVexposed children who survived infancy and remained HIV-free to 18 months of age had significantly more growth impairment compared to HIV-unexposed children. Third, HIV-associated biological maternal characteristics were strongly associated with infant mortality. In particular, maternal cytomegalovirus viraemia and inflammation during pregnancy were independently associated with infant mortality. Fourth, HIV-exposed but uninfected children had differences in immune development compared to children who are HIV-unexposed, characterised by increased CD8+ T-cell differentiation, activation, proliferation, senescence and exhaustion, higher soluble CD14 concentrations, and differences in proportions of monocyte subsets. Fifth, differences in immune parameters were strongly associated with late gestational exposure to antenatal cytomegalovirus viraemia and early acquisition cytomegalovirus infection in infancy. Overall, this thesis has highlighted the vulnerability of HIV-exposed children despite improvements in the availability of ART. Maternal cytomegalovirus viraemia and systemic inflammation are identified as critical associations of infant outcomes independently of HIV viraemia, highlighting future research avenues and potential new targets for interventions