Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

Broadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map a fitness model of HIV-1 interacting with broadly neutralizing antibodies using in vivo data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary trade-off between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance–cost trade-off curves as a measure of antibody performance in the presence of resistance evolution.

Josephson Junctions as Single Microwave Photon Counters: Simulation and Characterization

Detection of light dark matter, such as axion-like particles, puts stringent requirements on the efficiency and dark-count rates of microwave-photon detectors. The possibility of operating a current-biased Josephson junction as a single-microwave photon-detector was investigated through numerical simulations, and through an initial characterization of two Al junctions fabricated by shadow mask evaporation, done in a dilution refrigerator by measuring escape currents at different temperatures, from 40 mK up to the Al transition temperature. The escape dynamics of the junctions were reproduced in the simulation, including the dissipative effects. Inhibition of thermal activation was observed, leaving the macroscopic quantum tunneling as the dominant effect well beyond the crossover temperature.

Escape Dynamics of a Particle From a Purely-nonlinear Truncated Quartic Potential Well Under Harmonic Excitation

This paper focuses on the escape problem of a harmonically-forced classical particle from a purely-quartic truncated potential well. The latter corresponds to various engineering systems that involve purely cubic restoring force and absence of linear stiffness even under the assumption of small oscillations, such as pre-tensioned metal wires and springs, and compliant structural components made of polymer materials. This, in contrast to previous studieswhere the equivalent potential well could be treated as linear at first approximation under the assumption of small perturbations. Due to the strong nonlinearity of the current potential well, traditional analytical methods are inapplicable for describing the transient bounded and escape dynamics of the particle. The latter is analyzed in the framework of isolated resonance approximation by canonical transformation to action-angle (AA) variables and thecorresponding reduced resonance manifold (RM). The escape envelope is formulated analytically. Surprisingly, despite the essential nonlinearity of the well investigated, it exhibits a universal property of a sharp minimum due to the existence of multiple intersecting escape mechanisms. Unlike previous studies, three underlying mechanisms that govern the transient dynamics of the particle were identified: two maximum mechanisms and a saddle mechanism. The first two correspond to a gradual increase in the system's response amplitude for a proportional increase in the excitation intensity, and the latter corresponds to an abrupt increase in the system's response and therefore more potentially hazardous. The response of the particle is described in terms of energy-based response curves. The maximal transient energy is predicted analytically over the space of excitation parameters and described using iso-energy contours. All theoretical predictions are in complete agreement with numerical results.

Escape dynamics of active particles in multistable potentials

Rare transitions between long-lived metastable states underlie a great variety of physical, chemical and biological processes. Our quantitative understanding of reactive mechanisms has been driven forward by the insights of transition state theory and in particular by Kramers’ dynamical framework. Its predictions, however, do not apply to systems that feature non-conservative forces or correlated noise histories. An important class of such systems are active particles, prominent in both biology and nanotechnology. Here, we study the active escape dynamics of a silica nanoparticle trapped in a bistable potential. We introduce activity by applying an engineered stochastic force that emulates self-propulsion. Our experiments, supported by a theoretical analysis, reveal the existence of an optimal correlation time that maximises the transition rate. We discuss the origins of this active turnover, reminiscent of the much celebrated Kramers turnover. Our work establishes a versatile experimental platform to study single particle dynamics in non-equilibrium settings.

On the escape of a resonantly excited couple of particles from a potential well

The escape dynamics of a damped system of two coupled particles in a truncated potential well under biharmonic excitation are investigated. It is assumed that excitation frequencies are tuned to the modal natural frequency of the relative motion and to the modal frequency of the centre of mass on the bottom of the potential well. Although the escape is essentially a non-stationary process, the critical force strongly depends on the stationary amplitude of the relative vibrations within the pair of masses. The characteristic escape curve for the critical force moves up on the frequency-escape threshold plane with increasing relative vibrations, which can be interpreted as a stabilizing effect due to the high-frequency excitation. To obtain the results, new modelling techniques are suggested, including the reduction in the effect of the high-frequency excitation using a probability density function-based convolution approach and an energy-based approach for the description of the evolution of the slow variables. To validate the method, the coupled pair of particles is investigated with various model potentials.

Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody

ABSTRACTBroadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map an in vivo fitness landscape of HIV-1 interacting with broadly neutralizing antibodies, using data from a recent clinical trial. We identify two fitness factors, antibody dosage and viral load, that determine viral reproduction rates reproducibly across different hosts. The model successfully predicts the escape dynamics of HIV-1 in the course of an antibody treatment, including a characteristic frequency turnover between sensitive and resistant strains. This turnover is governed by a dosage-dependent fitness ranking, resulting from an evolutionary tradeoff between antibody resistance and its collateral cost in drug-free growth. Our analysis suggests resistance-cost tradeoff curves as a measure of antibody performance in the presence of resistance evolution.

Effect of Self-Oscillation on Escape Dynamics of Classical and Quantum Open Systems

We study the effect of self-oscillation on the escape dynamics of classical and quantum open systems by employing the system-plus-environment-plus-interaction model. For a damped free particle (system) with memory kernel function expressed by Zwanzig (J. Stat. Phys. 9, 215 (1973)), which is originated from a harmonic oscillator bath (environment) of Debye type with cut-off frequency wd, ergodicity breakdown is found because the velocity autocorrelation function oscillates in cosine function for asymptotic time. The steady escape rate of such a self-oscillated system from a metastable potential exhibits nonmonotonic dependence on wd, which denotes that there is an optimal cut-off frequency makes it maximal. Comparing results in classical and quantum regimes, the steady escape rate of a quantum open system reduces to a classical one with wd decreasing gradually, and quantum fluctuation indeed enhances the steady escape rate. The effect of a finite number of uncoupled harmonic oscillators N on the escape dynamics of a classical open system is also discussed.