An HLA-I signature favouring KIR-educated Natural Killer cells mediates immune control of HIV in children and contrasts with the HLA-B-restricted CD8+ T-cell-mediated immune control in adults

Abstract

Natural Killer (NK) cells contribute to HIV control in adults, but HLA-B-mediated T-cell activity has a more substantial impact on disease outcome. However, the HLA-B molecules influencing immune control in adults have less impact on paediatric infection. To investigate the contribution NK cells make to immune control, we studied >300 children living with HIV followed over two decades in South Africa. In children, HLA-B alleles associated with adult protection or disease-susceptibility did not have significant effects, whereas Bw4 (p = 0.003) and low HLA-A expression (p = 0.002) alleles were strongly associated with immunological and viral control. In a comparator adult cohort, Bw4 and HLA-A expression contributions to HIV disease outcome were dwarfed by those of protective and disease-susceptible HLA-B molecules. We next investigated the immunophenotype and effector functions of NK cells in a subset of these children using flow cytometry. Slow progression and better plasma viraemic control were also associated with high frequencies of less terminally differentiated NKG2A+NKp46+CD56^dim NK cells strongly responsive to cytokine stimulation and linked with the immunogenetic signature identified. Future studies are indicated to determine whether this signature associated with immune control in early life directly facilitates functional cure in children. In adults, immune control of HIV is strongly influenced by antiviral CD8+ T-cell responses restricted by ‘protective’ HLA class I molecules, such as HLA-B*57, and by ‘disease-susceptible’ HLA class I molecules such as HLA-B*58:02. By contrast, Natural Killer (NK) cells responses make a smaller, albeit significant, contribution. In this study, we evaluate in children living with HIV the contribution of NK cell responses to immune control of HIV, in an age group where HIV-specific CD8+ T-cell responses have less impact on disease outcome. A cohort of >300 therapy-naïve children living with HIV shows that a genetic signature favouring a KIR-education on NK cells is associated with slow progression and better viraemic control. Consistent with this, we observed control of HIV viraemia and lower total HIV DNA levels among children was associated with a less differentiated NKG2A+NKp46+ CD56^dim NK cell population that functionally was highly responsive to cytokine stimulation. Thus, the study identifies a signature that can impact future therapeutic strategies to achieve remission in children.