A role for Fas/FasL-dependent NK-mediated cytotoxicity in infants with perinatal HIV

Perinatal HIV infection occurs during a critical window of immune system development, yet its impact on innate immune responses in early life remains incompletely understood. This study examined natural killer (NK) cell phenotype, transcriptional profile, and function in infants living with perinatal (pHIV) and HIV-exposed uninfected (pHEU) peers from Mozambique. At pre-ART initiation, NK cells were expanded in pHIV, but overall NK cytotoxic activity appeared similar between groups. A key finding was the identification of the Fas/FasL pathway as a preferred mechanism for the NK cell-mediated killing of HIV-infected cells, while perforin-dependent killing was preferred in response to the highly NK sensitive K562 cell line. Infants with higher viral loads exhibited reduced <i>FasL</i> transcript expression, suggesting that impaired Fas/FasL signaling may limit effective early immune control. These results highlight a potentially underappreciated role for Fas/FasL in shaping antiviral immunity in pediatric HIV.