More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1.

Alison F Feder,Pleuni S Pennings,Robert W Shafer,Dmitri A Petrov,Susan P Holmes,Soo-Yon Rhee

doi:10.7554/elife.10670

Abstract

In the early days of HIV treatment, drug resistance occurred rapidly and predictably in all patients, but under modern treatments, resistance arises slowly, if at all. The probability of resistance should be controlled by the rate of generation of resistance mutations. If many adaptive mutations arise simultaneously, then adaptation proceeds by soft selective sweeps in which multiple adaptive mutations spread concomitantly, but if adaptive mutations occur rarely in the population, then a single adaptive mutation should spread alone in a hard selective sweep. Here, we use 6717 HIV-1 consensus sequences from patients treated with first-line therapies between 1989 and 2013 to confirm that the transition from fast to slow evolution of drug resistance was indeed accompanied with the expected transition from soft to hard selective sweeps. This suggests more generally that evolution proceeds via hard sweeps if resistance is unlikely and via soft sweeps if it is likely.

Highlights

In the first two decades of the HIV epidemic, HIV became a prime example of fast evolutionary change, especially because of the evolution of drug resistance quickly after initiation of treatment
To test whether a transition from soft to hard sweeps has occurred, we look at the relationship between fixed drug resistance mutations (DRMs) and genetic diversity across 29 common anti-retroviral drug regimens
We find that the extent of diversity reduction associated with drug resistance mutations varies with the clinical effectiveness of the treatment - effective drug treatments with low rates of virologic failure show strong reductions in diversity associated with each additional resistance mutation, a pattern more consistent with hard selective sweeps, whereas treatments that fail more often show no reduction in diversity, a pattern consistent with soft selective sweeps

Summary

Introduction

In the first two decades of the HIV epidemic, HIV became a prime example of fast evolutionary change, especially because of the evolution of drug resistance quickly after initiation of treatment. HIV treatments are more clinically effective and the evolution of drug resistance has become much slower and often does not occur for years if at all. The rate at which evolution occurs has been the subject of considerable recent interest in the evolutionary biology community. Population genetic theory suggests that whether populations evolve slowly or quickly is driven by the availability of adaptive mutations. In a large population with a high mutation rate, mutations may be available as standing genetic variation (pre-existing variation) or be generated anew every generation, allowing the population to adapt to its environment rapidly. If adaptive mutations are rare, because the population is small, the mutation rate is low, or only few specific mutations (or combinations of mutations) can help a population adapt, the population will likely adapt to its environment much more slowly

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