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Published on: January 22, 2019
A strategy for effective latent HIV reactivation using subtherapeutic drug doses
James Cotterell1,2, G Gregory Neely3,4
1The Garvan Institute for Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia. j.cotterell@crg.es.
Abstract:
Cell state switches underlie a plethora of biological phenomena and disease treatment strategies. Hence the ability to efficiently switch states in a chosen direction is of central importance in a number of scenarios. Increasing the concentration of an effector that results in a given switch is often limited by side effects. Approaches are thus increasingly sought to bypass these constraints, increasing the frequency of state switching without increasing the frequency of the side effect. Here, we employ dynamical systems theory to uncover a simple strategy as to how to maximize the probability of reactivating latent Human immunodeficiency virus (HIV) whilst maintaining minimal side effects. We demonstrate that continuous supply of an effector is significantly more likely to result in a switch with minimal side effects than the same effector supplied in temporally discrete doses. Importantly this continual dosage is likely to occur far below the Minimum effective dose at a concentration that has classically been thought subtherapeutic. We therefore suggest that in many interventional settings there exists potential to reduce drug dose much further than has previously been thought possible yet still maintaining efficacy.
Insights
Continuous effector supply, not discrete doses, maximizes cell state switching like latent Human immunodeficiency virus (HIV) reactivation, even at sub-therapeutic levels, minimizing side effects.
Area of Science:
- Cellular dynamics and biological switches
- Virology and disease intervention strategies
Background:
- Cell state switching is crucial for biological processes and disease treatments.
- Current methods for inducing state switches are often limited by effector side effects.
- There is a need for strategies to enhance state switching frequency while minimizing adverse effects.
Purpose of the Study:
- To uncover a strategy for maximizing cell state switching probability.
- To specifically address the reactivation of latent Human immunodeficiency virus (HIV).
- To achieve efficient state switching with minimal side effects.
Main Methods:
- Application of dynamical systems theory to model cell state transitions.
- Comparison of continuous effector supply versus discrete dosing strategies.
- Analysis of effector concentration effects on switching probability and side effects.
Main Results:
- Continuous effector supply significantly increases the probability of state switching compared to discrete doses.
- This continuous strategy is effective even at concentrations below the classically defined Minimum effective dose.
- Minimal side effects are observed with continuous, low-dose effector administration.
Conclusions:
- Continuous effector administration is a superior strategy for inducing cell state switches, including HIV reactivation.
- Lower, continuous drug doses can be therapeutically effective while reducing side effects.
- This approach offers potential for optimizing therapeutic interventions by reducing drug dosage.
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