Fig. 4: The optimal model for AMP viral loads incorporates VRC01 concentration and acquired isolate sensitivity to VRC01, as well as fitness costs and in vivo potency reduction.

a The viral dynamics and PKPD (PKPD-V) mathematical model used to impute viral load curves⁴³. Susceptible cells S are born and die in the absence of virus (rates \({{{{{{\rm{\alpha }}}}}}}_{{{{{{\rm{S}}}}}}}\) and \({{{{{{\rm{\delta }}}}}}}_{{{{{{\rm{S}}}}}}}\), respectively) and are infected upon exposure to virus V with infectivity rate \({{{{{\rm{\beta }}}}}}\), infected cells \({{{{{\rm{I}}}}}}\) die nonlinearly with rate \({\delta }_{{{{{{\rm{I}}}}}}}\left({{{{{\rm{I}}}}}}\right)=\kappa {I}^{n}\), virions are produced with rate \({{{{{\rm{\pi }}}}}}\) and cleared with rate \({{{{{\rm{\gamma }}}}}}\). VRC01 concentration is predicted by the same PK model as in Fig. 2a and is connected into the viral dynamics through the PD model where VRC01 concentration reduces cell infection events, \({{{{{\rm{\beta }}}}}}({{{{{{\rm{C}}}}}}}_{{{{{{\rm{t}}}}}}},{{{{{\rm{IC}}}}}}80,{{{{{\rm{\rho }}}}}})\) based on IC80 of acquired virus and in vivo potency reduction. The indirect effect implies viral production is lowered for more resistant isolates \({{{{{\rm{\pi }}}}}}({{{{{\rm{IC}}}}}}80)\). b Eight examples of participants with simultaneous PK and viral load fits relative to first positive viral load (see all in Supplementary Data 1 & 2). Dots represent observed concentrations and viral loads, solid lines represent model output, and dashed lines represent counterfactual model simulations with no potency reduction. PK curve colors indicate treatment arm (light blue: 10 mg/kg; green: 30 mg/kg). Viral load curve colors indicate acquired virus sensitivity to VRC01 (blue: VRC01 sensitive; orange: VRC01 resistant). Annotations provide definitions for model-based metrics. Horizontal gray lines in PK plots contextualize serum concentrations relative to in vitro IC80s. c Predicted % of cellular infections blocked at a given titer estimated from in vivo viral load data (solid red) compared to in vitro predicted neutralization (dashed black). The pink shading around the solid red curve denotes 95% confidence intervals. The difference between the curves illustrates the 600-fold potency reduction in vivo.