Background
Many HIV cure trials use time-to-rebound during an analytic treatment interruption (ATI) as a primary outcome measurement. In a previously described ATI study with no intervention, the fraction of replication-competent outgrowth viruses neutralized by contemporaneous autologous neutralizing antibodies (aNAbs) prior to ART interruption correlated with time to rebound. Therefore, aNAbs may also contribute to delayed rebound in trials that include a broadly neutralizing antibody (bNAb) intervention or other interventions. Participants in the NCT03588715 (BEAT2) clinical trial received six infusions of the bNAbs 3BNC117 and 10-1074, and thirty doses of IFNa2b. Following cessation of all immunotherapies, BEAT2 participants had variable times to rebound (4-25 weeks), and we hypothesized that aNAbs may be a critical contributing factor.
Methods
Inhibition of viral outgrowth by aNAbs was assessed at baseline using a modified quantitative viral outgrowth assay in which resting CD4+ T cells were activated by PHA and cultured in the presence of contemporaneous autologous IgG, HIV-negative donor IgG, or no IgG for 14 days. Viral outgrowth was measured by HIV-1 p24 ELISA and env genes sequenced.
Results
The fraction of replication-competent outgrowth viruses neutralized by contemporaneous aNAbs at baseline varied widely (0 to 100%) among participants and correlated significantly (p=0.0342) with time-to-rebound following cessation of all immunotherapies. HIV-1 env sequencing and phylogenetic analyses revealed critical differences between aNAb-sensitive and aNAb-resistant outgrowth virus. aNAb-resistant reservoir variants detected prior to the ATI may be genetically similar or identical to rebound virus.
Conclusions
The study participants had a variable fraction of inducible, replication-competent reservoir viruses neutralized by contemporaneous aNAbs prior to receiving immunotherapy (bNAbs and IFNa2b) and undergoing ART interruption. Higher proportions of replication-competent outgrowth viruses neutralized by aNAbs was associated with a more delayed time-to-rebound following cessation of all immunotherapies. ATI studies must consider the role of pre-existing aNAbs in potentially confounding time-to-rebound measurements.
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