BACKGROUND: Case reports of post-treatment control of HIV in children initiating early combination antiretroviral therapy (cART) prompt the hypothesis that a subset of very-early treated children can achieve post-treatment control without additional interventions. To test this, and identify underlying control mechanisms, we conducted a longitudinal study in KwaZulu-Natal, South Africa of 281 mother-child pairs monitored from delivery following in utero HIV transmission.
METHODS: The study period was 2015-2023. All infants received ART at birth, and >92% of infants received cART prior to birth via placental transfer of maternal cART. ART adherence was monitored via plasma cART concentrations determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS), maternal history, pill-counting and pharmacy records. After generating chimeric gag-protease-NL4-3 viruses following viral RNA isolation and nested RT-PCR amplification of mother and child gag-protease from baseline plasma, type I interferon (IFN-I) sensitivity and replicative capacity of transmitted viruses were determined using the reporter cell lines U87-snLuc/EGFP and CEM-GXR, respectively.
RESULTS: Maintenance of aviraemia was highly dependent on cART adherence, irrespective of infant baseline plasma viral load. Exceptionally, five males were identified in whom aviraemia was maintained (for >3m to >19m) despite persistent cART non-adherence. By contrast, the majority (60%) of the cohort was female (p=0.01). Higher rates of in utero transmission to female fetuses was associated with female susceptibility to IFN-I resistant virus (p<0.0001) that tended to have low viral replication capacity (p=0.0001). While viruses transmitted to male fetuses overall were typically IFN-I sensitive and of higher replicative capacity, those transmitted to males maintaining aviraemia despite persistent cART non-adherence had low replicative capacity (p<0.0001; Figure: circled are the 4 baseline viruses from the 5 males that were analysed; all 4 were replication competent, in one case replication capacity was <LoD).

CONCLUSIONS: These data suggest that early-life innate immune sex differences contribute significantly to post-treatment control in children living with HIV.