Background:
To evaluate possible alternatives to ART among children living with HIV, the Tatelo clinical trial administered two broadly-neutralizing antibodies to children in Botswana with HIV clade C infection who had initiated ART at birth. Here we describe a high-resolution, cross-sectional and longitudinal analysis of the proviral reservoir landscape in Taleo participants.
Methods:
Children were initially followed in the Early Infant Treatment (EIT) cohort, receiving continuous ART from birth; those entering Tatelo had HIV-1 RNA < 40 c/mL for ≥24 weeks prior to entry and were >96 wks of age. Tatelo participants received ART plus VRC01LS and 10-1074 (dosed every 4 wks) for at least 8 weeks, after which ART was stopped. Peripheral blood mononuclear cells were collected every 2-4 weeks. HIV-1 proviruses and chromosomal integration sites were analyzed using FLIP-seq and MIP-seq.
Results:
Of 25 children treated with VRC01-LS and 10-1074 alone, eleven (44%) maintained HIV RNA < 400 c/mL through 24 weeks (controllers) and 14 (56%) had viral rebound >400 c/mL (rebounders). In total, 592 proviral genomes (216 intact, 376 defective) were obtained; 31 integration sites of intact proviruses and 29 integration sites of defective proviruses were identified. Frequencies of total, intact and defective proviruses at birth were lower in controllers than in rebounders. No significant changes in intact, defective and total proviral frequencies were observed in controllers before and after bNAb treatment. Rebounders demonstrated a significantly higher reservoir of intact proviruses immediately prior to or at virological rebound compared to Tatelo entry (p=0.004). Proviruses were preferentially integrated into genes, and evidence for clonal expansion of proviruses with identical integration sites was detected in multiple children. In two controllers with high frequencies of viral reservoir cells, and one rebounder with low HIV RNA rebound (742 copies/mL), intact proviruses were preferentially (67%) integrated in centromeric/satellite DNA, ZNF genes and non-genic DNA.
Conclusions:
In children with early initiation of ART, very low viral reservoirs were observed in controllers, without detectable differences in proviral reservoir size before and after bNAb treatment. In contrast, intact and defective proviruses were more commonly identifiable among rebounders beginning at birth, and increased in frequency between bNab initiation and rebound.