Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01.

E Fabian Cardozo-Ojeda,Alan S Perelson

doi:10.3389/fimmu.2021.710012

E Fabian Cardozo-Ojeda, Alan S Perelson

Open Access

https://doi.org/10.3389/fimmu.2021.710012

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Abstract

VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.

Highlights

Passive administration of broadly neutralizing antibodies in infected humanized-mice, macaques and humans has suggested that bnAb infusion may be a therapeutic modality against HIV-1 infection [1,2,3]
After infusion of 40 mg/kg of VRC01, the serum antibody concentration decayed in a biphasic manner, similar to decays previously observed with other monoclonal antibodies [8, 16]
As done previously [16, 17], we modeled these dynamics by using a two-compartment pharmacokinetic model presented in equation [1], where A1 and A2 represent the concentration of VRC01 in compartments one and two, respectively

Summary

Introduction

Passive administration of broadly neutralizing antibodies (bnAbs) in infected humanized-mice, macaques and humans has suggested that bnAb infusion may be a therapeutic modality against HIV-1 infection [1,2,3]. Safety and effect of VRC01 on plasma viral load, this antibody was infused into HIV-1 chronically infected individuals in a phase 1 clinical trial [1, 8]. After a single infusion of 40 mg/kg of VRC01, the plasma viral load was reduced by more than 1-log in 6/8 infected individuals, but there was no significant response in the other two participants [1]. The other three responding participants presented a steady or an initial increase in the viral load to values higher than baseline. Both patterns were followed by a decline in viral load that persisted but slowly returned to baseline as the VRC01 concentration declined (see Figure 1)

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