Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

PGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants in this trial with the sampled rebound viruses being entirely resistant to PGT121 mediated neutralization. However, two individuals experienced long-term ART-free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Here, we develop mathematical models of the HIV-1 dynamics during this phase I clinical trial. We utilize these models to understand the dynamics leading to PGT121 resistance and to identify the mechanisms driving the observed long-term viral control. Our modeling highlights the importance of the relative fitness difference between PGT121 sensitive and resistant subpopulations prior to treatment. Specifically, by fitting our models to data, we identify the treatment-induced competitive advantage of previously existing or newly generated resistant population as a primary driver of resistance. Finally, our modeling emphasizes the high neutralization ability of PGT121 in both participants who exhibited long-term viral control.Author summary: Human immunodeficiency virus (HIV)-1-specific broadly neutralizing antibodies (bnAbs) have been proposed as a novel treatment modality for the treatment and prevention of HIV-1 infection. However, bnAb monotherapy has not led to sustained viral control during treatment of HIV-1 positive individuals with viral rebound being driven by the emergence of bnAb resistance. We use mathematical models to study resistance to the V3-glycan-specific antibody PGT121 in a phase I clinical trial. We found that the level of pre-existing resistance as well as the evolutionary dynamics of PGT121 resistant and sensitive viral subpopulations drive the rebound of treatment resistant virus following a single administration of PGT121. Further, our model identifies the high neutralization potency of PGT121 as a main driver of the observed long-term ART-free viral suppression observed in two trial participants.