Background:
Broadly neutralizing antibodies (bNAbs) display strong antiviral activity by targeting HIV Envelope (Env) with high potency and breadth. However, Env diversity can lead to natural resistance, creating challenges for the use of bNAbs as antiviral therapies, and posing the need to screen participants for susceptibility to bNAbs. We compared genotypic and phenotypic analyses to determine participant susceptibility to GS-5423 (3BNC117-LS) and GS-2872 (10-1074-LS) prior to enrollment into a Phase 1b study evaluating their safety, tolerability, and efficacy in combination with the HIV capsid inhibitor lenacapavir dosed every 6 months in ART-suppressed people with HIV (PWH).
Methods:
PBMCs from 124 participants obtained at screening were used to assess susceptibility to GS-5423 and GS-2872 using 3 different methods. Phenotypic analysis of proviral DNA from PBMCs was performed using the PhenoSense mAb DNA assay (Monogram), with susceptibility defined as IC90 ≤2 μg/mL. Viral outgrowth in combination with the PhenoSense mAb RNA assay (Monogram) was performed on available PBMCs from 92 participants. The HIV Env gene from proviral DNA in PBMCs was genotyped using deep sequencing (Seq-IT) and susceptibility to bNAbs predicted using previously described Env amino acid signatures (Moldt, B. et al. 2021).
Results:
PhenoSense mAb DNA assay results were obtained for 109 of 124 participants (15 assay failures). 75% of participants were susceptible to GS-5423, 65% to GS-2872, and 50% to both bNAbs. Viral outgrowth >1,000 copies/ml was observed for 48 of 92 samples. Phenotypic susceptibility was obtained for 35 of those samples, with 49% susceptible to GS-5423, 69% to GS-2872, and 31% to both bNAbs. Phenotypic susceptibilities determined for outgrowth virus and proviruses were correlated (Fig. 1) (GS-5423 r=0.79, P< 0.0001; GS-2872 r=0.75, P< 0.0001). Genotypic susceptibility to GS-5423 and GS-2872 was determined for 59 of 109 proviral sequences with phenotypic data. Proviral genotypic signatures predicted phenotypic susceptibility of proviruses and outgrowth virus with high specificity (93-100% GS-5423, 71-96% GS-2872), but low sensitivity (24-11% GS-5423, 76-8% GS-2872).
Conclusions:
We compared 3 different methods to determine susceptibility to GS-5423 and GS-2872 in ART-suppressed participants. These data demonstrate that the susceptibility to bNAbs is correlated between all 3 assay types and may be useful in further refining the criteria for selecting PWH who could be eligible for bNAbs studies.
Fig. 1: Correlation of neutralization IC90 values between outgrowth viruses and proviruses 