HIV-1 infection in Kenyan infants : natural history and T cell responses

• Main Author: Slyker, Jennifer Ann
• Published: Open University 2007
• Subjects: 616.9
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487159

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. Afri can cohorts have reported the highest rates of mortality, from 20-50% at 2 years oflife. 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, i 9.4% 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;isk 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 mv-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-l 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 magni1ude than observed in the CD8 subset. HIV-1 specific CD8 T cells were studied in a subset of infants using IFN-y ELISpot assays and tetramer staining. Very high frequencies of HIV-1 specific CD8 T c~lls 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-y production is lowercompared to adult cells. Reduced functional capacity may explain the inability of infant T cell responses to contain HIV-1 viral load.