HIV-1 resistance to neutralizing antibodies: Determination of antibody concentrations leading to escape mutant evolution.
Broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) are considered vital components of novel therapeutics and blueprints for vaccine research. Yet escape to even the most potent of these antibodies is imminent in natural infection. Measures to define antibody efficacy and prevent mutant selection are thus urgently needed. Here, we derive a mathematical framework to predict the concentration ranges for which antibody escape variants can outcompete their viral ancestors, referred to as mutant selection window (MSW). When determining the MSW, we focus on the differential efficacy of neutralizing antibodies against HIV-1 in two canonical infection routes, free-virus infection and cell-cell transmission. The latter has proven highly effective in vitro suggesting its importance for both in vivo spread as well as for escaping targeted intervention strategies. We observed a range of MSW patterns that highlight the potential of mutants to arise in both transmission pathways and over wide concentration ranges. Most importantly, we found that only when the arising mutant has both, residual sensitivity to the neutralizing antibody and reduced infectivity compared to the parental virus, antibody dosing outside of the MSW to restrict mutant selection is possible. Emergence of mutants that provide complete escape and have no considerable fitness loss cannot be prevented by adjusting antibody doses. The latter may in part explain the ubiquitous resistance to neutralizing antibodies observed in natural infection and antibody treatment. Based on our findings, combinations of antibodies targeting different epitopes should be favored for antibody-based interventions as this may render complete resistance less likely to occur and also increase chances that multiple escapes result in severe fitness loss of the virus making longer-term antibody treatment more feasible.
Institute of Medical Virology, University of Zurich, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. Electronic address: carsten.magnus@bsse.ethz.ch.
Carsten
C
Magnus
Institute of Medical Virology, University of Zurich, Switzerland. Electronic address: reh.lucia@virology.uzh.ch.
Lucia
L
Reh
Institute of Medical Virology, University of Zurich, Switzerland. Electronic address: trkola.alexandra@virology.uzh.ch.
Alexandra
A
Trkola
D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004306:Dose-Response Relationship, Immunologic; D024882:Drug Resistance, Viral / Q000235:genetics* / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects*; D015233:Models, Statistical; D009154:Mutation; D009500:Neutralization Tests; D012641:Selection, Genetic; D014774:Virulence
D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies
Broadly neutralizing antibodies; Cell–cell transmission; Free-virus transmission; HIV-1 neutralization; Mathematical models of resistance evolution; Mutant selection window