HIV-1 Infection in Kenyan Infants: Natural History and T cell Responses

Abstract

This thesis describes human immunodeficiency virus type 1 (HIV-1) infection in Kenyan infants. Paediatric HIV-1 infection causes rapid disease progression in the absence of antiretroviral (ARV) therapy. African cohorts have reported the highest rates of mortality, from 20-50% at 2 years of life. Understanding the pathogenesis in HIV-1 infected children is important to the design of prevention, treatment, and vaccination strategies. A cohort of 476 Kenyan children born to HIV-1 infected women was studied longitudinally from the time of birth to 24 months. Despite the provision of ARVs to prevent mother-to-child transmission, 19.4% of infants became infected with HIV-1. Infant HIV-1 infection resulted in persistently high levels of viraemia and rapid CD4 depletion. Cumulative mortality at 2 years was 54%. Peak and set-point HIV-1 viral load, and CD4% at 6 months were predictors of 2-year mortality. Co-infection with cytomegalovirus (CMV) before the age of 1 month was also associated with increased risk of death. Infants with HIV-1 infection had poorly contained CMV viraemia in comparison with HIV-1 exposed uninfected controls. Multicolour flow cytometry was used to describe the phenotype of T cells during primary viral infection. Both CMV and HIV-1 infection resulted in dynamic redistribution of T cell populations. High frequencies of activated, apoptotic vulnerable, differentiating CD8 T cells were observed concurrent to acute infection with either HIV-1 or CMV. Co-infection with both viruses resulted in even more profound changes in cellular phenotype. CD4 T cell phenotype was also affected by acute viral infection, but at a much lower magnitude than observed in the CD8 subset. HIV-1 specific CD8 T cells were studied in a subset of infants using IFN-γ ELISpot assays and tetramer staining. Very high frequencies of HIV-1 specific CD8 T cells were identified with tetramer staining, and these cells resembled adult T cell responses in magnitude and phenotype. ELISpot assays revealed weak responses in infants less than 6 months old that increased with age. These data suggest that HIV-1 specific CD8 T cell responses can be generated during acute infection in infants, but IFN-γ production is lower compared to adult cells. Reduced functional capacity may explain the inability of infant T cell responses to contain HIV-1 viral load.