Natural killer cells in pediatric HIV cure strategies: from viral control to immunotherapeutics

Purpose of review: Perinatal HIV infection occurs during a critical window of immune development, in a predominantly naïve immune system, resulting in distinct and unique virologic and immunologic outcomes compared with adult-acquired infection. Innate immunity and specifically natural killer (NK) cells play a role in early viral control and critically shape both size and composition of the HIV reservoir established in infancy. This review examines how NK cell function during acute infection and treatment interruption may contribute to virological outcomes. Recent findings: Emerging data show that NK cell phenotypic and functional diversity associates with reservoir size and persistence. Immune-genetic factors, including HLA and KIR interactions and sex-specific differences, can significantly modulate NK-mediated HIV control. Studies also highlight how perinatal HIV exposure and co-infections alter innate immune networks involving monocytes and CD8 T cells, further influencing reservoir dynamics. Summary: Insights into pediatric NK cell immunity reveal unique mechanisms of early HIV control and reservoir shaping that differ from adults. Understanding how NK cell function influences virological outcomes during acute infection and analytic treatment interruption (ATI) provides a critical foundation for designing cure strategies tailored to children. These include leveraging antibody-based interventions and emerging NK-directed immunotherapies to enhance reservoir clearance and support safer, more effective ATI-informed cure approaches.