Pre-existing resistance is a barrier to the efficacy of broadly neutralizing antibodies (bnAbs) for treatment and cure of HIV infection. Here, we determine the range of baseline susceptibilities to bnAbs in clinical development and assess the PhenoSense HIV nAb Assay’s predictive capacity in plasma virus and proviral DNA samples.
HIV envelopes derived from pre-ART plasma and PBMCs from 1 and 3 years of ART from each of 65 chronically HIV-infected participants of the ART naïve trial A5257 were tested for neutralization susceptibility to seven bnAbs (VRC01, VRC07.523LS, 3BNC117, N6, 10-1074, CAP256-VRC26.25, 10E8) using the PhenoSense nAb assay, which generates pseudovirions from plasma vRNA or PBMC proviral DNA-derived HIV envelopes. PBMCs from 9 participants at entry to A5340, which evaluated VRC01 during ART interruption, were also tested. Rank-based Spearman Correlation and Fisher’s exact tests were used for statistical analyses.
Participants’ median CD4 count was 350 cells/mm3 and 40% had a baseline VL >100,000 copies/ml. IC50s varied more than 3 logs for each bnAb, but pre-ART plasma, year 1 and 3 PBMC values were highly correlated (Spearman r= 0.62-0.95, P<0.001 for all), with modestly lower IC50s in PBMC samples. Correlations for titers against VRC01 in the 3 samples are shown in Figure 1. Susceptibilities within the CD4 binding site bnAbs were correlated (r=0.71-0.86, P<0.001 for pre-ART plasma). No significant relationships were found between bnAb classes, except a modest correlation between CD4bs bnAbs and 10-1074 (r= 0.29-0.4, P=0.002-0.023). Among the A5340 samples, VRC01 IC50s from entry PBMCs correlated with published pre-ART plasma IC50s available for 5 participants (Spearman r=0.9, P=0.04). In 9 participants with entry PBMCs, VRC01 IC50s did not significantly correlate with time to rebound (Spearman r=-0.35, P=0.37), but IC50<0.5 µg/mL was associated with delayed time to rebound (>8 weeks) (P=0.0278).
We found a wide range in baseline neutralization susceptibilities to clinically relevant bnAbs with highly correlated values across plasma and PBMC-derived samples over 3 years of ART. In A5340, PhenoSense nAb susceptibilities on entry PBMCs were similar to published pre-ART values and IC50<0.5 µg/mL was associated with delayed rebound after ATI. Results support the utility of screening for neutralization susceptibility prior to therapeutic bnAb use and suggest PhenoSense nAb PBMC testing may be a valid approach in suppressed individuals.