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

Feder AF, Rhee SY, Holmes SP, Shafer RW, Petrov DA, Pennings PS - Elife (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Stanford University, Stanford, United States.

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.

No MeSH data available.


Related in: MedlinePlus

Nonparametric test shows negative correlation between treatment effectiveness and  when sequences with any number of DRMs are included.This figure is analogous with Figure 4 from the main text, but in this case, the data is not truncated to only include the patients with 4 or fewer DRMs. The  coefficients are taken from the GLMM shown in Figure 3—figure supplement 2A and B. The figure caption is otherwise shared with Figure 4.DOI:http://dx.doi.org/10.7554/eLife.10670.014
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fig4s2: Nonparametric test shows negative correlation between treatment effectiveness and when sequences with any number of DRMs are included.This figure is analogous with Figure 4 from the main text, but in this case, the data is not truncated to only include the patients with 4 or fewer DRMs. The coefficients are taken from the GLMM shown in Figure 3—figure supplement 2A and B. The figure caption is otherwise shared with Figure 4.DOI:http://dx.doi.org/10.7554/eLife.10670.014

Mentions: We find a similar negative relationship between and treatment effectiveness when including 45 sequences before 1995 (Figure 4—figure supplement 1) and including sequences with more than 4 DRMs (Figure 4—figure supplement 2).


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

Feder AF, Rhee SY, Holmes SP, Shafer RW, Petrov DA, Pennings PS - Elife (2016)

Nonparametric test shows negative correlation between treatment effectiveness and  when sequences with any number of DRMs are included.This figure is analogous with Figure 4 from the main text, but in this case, the data is not truncated to only include the patients with 4 or fewer DRMs. The  coefficients are taken from the GLMM shown in Figure 3—figure supplement 2A and B. The figure caption is otherwise shared with Figure 4.DOI:http://dx.doi.org/10.7554/eLife.10670.014
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764592&req=5

fig4s2: Nonparametric test shows negative correlation between treatment effectiveness and when sequences with any number of DRMs are included.This figure is analogous with Figure 4 from the main text, but in this case, the data is not truncated to only include the patients with 4 or fewer DRMs. The coefficients are taken from the GLMM shown in Figure 3—figure supplement 2A and B. The figure caption is otherwise shared with Figure 4.DOI:http://dx.doi.org/10.7554/eLife.10670.014
Mentions: We find a similar negative relationship between and treatment effectiveness when including 45 sequences before 1995 (Figure 4—figure supplement 1) and including sequences with more than 4 DRMs (Figure 4—figure supplement 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Stanford University, Stanford, United States.

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.

No MeSH data available.


Related in: MedlinePlus