Biology subjects

Antal, T.

Publications and source records attributed to Antal, T..

2 recordsLinked to original sources

bioRxiv2018

Interference with HIV infection of the first cell is essential for viral clearance in a pre-exposure prophylaxis model

Pre-exposure prophylaxis (PrEP) uses relatively weak HIV inhibition to reduce transmission between individuals. Why this approach is successful is unclear. Here we derive and experimentally validate a mathematical model for predicting infection clearance with PrEP based on the measured effect of a drug on the HIV replication ratio and number of initial infected cells. We tested the model by inhibiting low dose HIV infection with tenofovir, which reduces infection frequency per cell, and atazanavir, which reduces the cellular burst size of viable virions. Both drugs were at concentrations which allowed similar HIV replication. Reducing infection frequency dramatically increased infection clearance, while reducing burst size did not. This indicates that initial infection is vulnerable to inhibition before it infects the first cell, but not thereafter. Our model explains why PrEP is potent at drug concentrations which are ineffective against established infection, and provides a framework to test drug effectiveness for PrEP.

bioinformatics↗

bioRxiv2018

Competing paths over fitness valleys in growing populations

Investigating the emergence of a particular cell type is a recurring theme in models of growing cellular populations. The evolution of resistance to therapy is a classic example. Common questions are: when does the cell type first occur, and via which sequence of steps is it most likely to emerge? For growing populations, these questions can be formulated in a general framework of branching processes spreading through a graph from a root to a target vertex. Cells have a particular fitness value on each vertex and can transition along edges at specific rates. Vertices represents cell states, say genotypes or physical locations, while possible transitions are acquiring a mutation or cell migration. We focus on the setting where cells at the root vertex have the highest fitness and transition rates are small. Simple formulas are derived for the time to reach the target vertex and for the probability that it is reached along a given path in the graph. We demonstrate our results on several scenarios relevant to the emergence of drug resistance, including: the orderings of resistance-conferring mutations in bacteria and the impact of imperfect drug penetration in cancer.

evolutionary biology↗