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

摘要

In the early days of HIV therapy, the strains of the virus that infected patients frequently evolved drug resistance and the therapies would often eventually fail. These treatments generally involved using a single anti-viral drug. Nowadays, better therapies involving combinations of several anti-viral drugs are available and drug resistance in HIV is a much rarer occurrence. This means that now a particular therapy may be an effective treatment for an HIV-infected individual over much longer periods of time. A theory of population genetics predicts that when it is easy for a population to acquire a beneficial genetic mutation – like one that provides drug resistance – multiple versions of that mutation may spread in the population at the same time. This is called a soft selective sweep. However, when beneficial mutations occur only rarely, it is expected that only one version of that mutation will take over in a population, which is known as a hard selective sweep. Here, Feder et al. test this theory using data from 6717 patients with HIV who were treated between 1989 and 2013 using a variety of different drug therapies. The experiments aimed to find out whether the transition from the older drug therapies –where the virus frequently acquired resistance – to the newer, more effective drugs was associated with a transition from soft to hard sweeps. Feder et al. find that HIV more often evolved drug resistance via soft sweeps in patients treated with the less effective drug combinations (like those given in the early days of HIV treatment), while hard sweeps were more common with the more effective drug combinations. This suggests that good drug combinations may allow fewer drug resistance mutations to occur in the HIV population within a patient. This may be because there are fewer virus particles in these patients, or because the specific combinations of mutations that provide resistance occur less often. Feder et al.’s findings are a step towards understanding why modern HIV treatments work so well, which will ultimately help us find better treatments for other infectious diseases.