Natural killer cell dysfunction in HIV-exposed uninfected infants correlates with acquisition of lower respiratory tract infection

Abstract

Abstract Background HIV-exposed uninfected infants (HEU) have higher rates of severe and fatal lower respiratory tract infections (LRTI) than HIV-unexposed infants (HUU), but their antibody responses to vaccines and infections do not differ. We hypothesized that natural killer cells (NK) are impaired in HEU and may predispose them to severe LRTI. Methods Peripheral blood mononuclear cells (PBMC) from Brazilian HEU and HUU were cryopreserved at birth and 6 months. NK phenotype and function assessed by flow cytometry after overnight incubation with and without K562 cells were compared among HEU who developed LRTI in the first 6 months of life (LRTI+), HEU who did not (LRTI−) and HUU, using Mann Whitney tests. Results The proportion of NK among PBMC was lower in 13 HEU vs. 22 HUU at birth (1.7% vs. 10.3%, p<0.0001) and in 51 HEU vs. 72 HUU at 6 months (3.1% vs. 4.6%, p=0.0008). The proportion of stimulated NK that upregulated IFNγ (after subtraction of unstimulated controls) was lower in HEU vs. HUU at birth (0.8% vs. 2.6%, p=0.03) and at 6 months (4.1% vs. 8.5%, p=0.0008). In addition, 6 LRTI+ and 7 LRTI− HEUs differed at birth by the following: 1) K562-specific lysis was lower in LRTI+ vs. LRTI− HEU (5.6% vs. 9.9%, p=0.046); 2) The proportion of stimulated NK that upregulated IFNγ was lower in LRTI+ HEU vs. HUU (0.6% vs. 2.6%, p=0.01), but not in LRTI− HEU (2.5%); 3) Perforin upregulation of stimulated NK was absent in LRTI+ HEU (−5.9%), but present in HUU (4.6%, p=0.01 vs. LRTI+ HEU) and in LRTI− HEU (2.5%). At 6 months, there were no differences between LRTI+ and LRTI− HEU. Conclusion NK numbers and function are impaired in HEU. Poor NK function at birth is associated with acquisition of LRTI in the first 6 months of life and may predict infectious complications in HEU.