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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

Effect of multiple DRMs on sequence diversity separated by subtype.Average diversity level of sequences are plotted conditioned on number of fixed drug resistance mutations present separately by all the subtypes with more than 100 associated HIV populations. Means  SE are plotted among all the D-PCR dataset.DOI:http://dx.doi.org/10.7554/eLife.10670.006
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fig2s2: Effect of multiple DRMs on sequence diversity separated by subtype.Average diversity level of sequences are plotted conditioned on number of fixed drug resistance mutations present separately by all the subtypes with more than 100 associated HIV populations. Means SE are plotted among all the D-PCR dataset.DOI:http://dx.doi.org/10.7554/eLife.10670.006

Mentions: Second, we looked at the effect of multiple DRMs on within-patient diversity, as we hypothesize that multiple fixed DRMs may decrease diversity even more than a single DRM. This could result from sequential selective sweeps of single DRMs each reducing diversity, or from a single selective sweep that fixes multiple DRMs. Indeed, we find that for sequences that have between 0 and 4 DRMs, additional DRMs are associated with reduced genetic diversity (Figure 2B, p-value for -test between diversity among sequences with 0 versus 1 is 7.2 × 10−4, between 1 and 2 is 1.6 × 10−5, between 2 and 3 is 1.1× 10−2, between 3 and 4 is 2.5 × 10−3). After 4 DRMs, subsequent DRMs do not significantly reduce diversity further. The observed pattern of DRMs associated with reduced diversity is mainly driven by the patients receiving NNRTI or boosted PI-based treatments, as can be seen when separating the above analysis by drug treatment category (Figure 2—figure supplement 1C,D). Among patients treated with NRTIs alone or with unboosted PIs, this pattern is much less clear (Figure 2—figure supplement 1A,B). The observed pattern holds across the each of the most common subtypes separately (Figure 2—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)

Effect of multiple DRMs on sequence diversity separated by subtype.Average diversity level of sequences are plotted conditioned on number of fixed drug resistance mutations present separately by all the subtypes with more than 100 associated HIV populations. Means  SE are plotted among all the D-PCR dataset.DOI:http://dx.doi.org/10.7554/eLife.10670.006
© Copyright Policy
Related In: Results  -  Collection

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

fig2s2: Effect of multiple DRMs on sequence diversity separated by subtype.Average diversity level of sequences are plotted conditioned on number of fixed drug resistance mutations present separately by all the subtypes with more than 100 associated HIV populations. Means SE are plotted among all the D-PCR dataset.DOI:http://dx.doi.org/10.7554/eLife.10670.006
Mentions: Second, we looked at the effect of multiple DRMs on within-patient diversity, as we hypothesize that multiple fixed DRMs may decrease diversity even more than a single DRM. This could result from sequential selective sweeps of single DRMs each reducing diversity, or from a single selective sweep that fixes multiple DRMs. Indeed, we find that for sequences that have between 0 and 4 DRMs, additional DRMs are associated with reduced genetic diversity (Figure 2B, p-value for -test between diversity among sequences with 0 versus 1 is 7.2 × 10−4, between 1 and 2 is 1.6 × 10−5, between 2 and 3 is 1.1× 10−2, between 3 and 4 is 2.5 × 10−3). After 4 DRMs, subsequent DRMs do not significantly reduce diversity further. The observed pattern of DRMs associated with reduced diversity is mainly driven by the patients receiving NNRTI or boosted PI-based treatments, as can be seen when separating the above analysis by drug treatment category (Figure 2—figure supplement 1C,D). Among patients treated with NRTIs alone or with unboosted PIs, this pattern is much less clear (Figure 2—figure supplement 1A,B). The observed pattern holds across the each of the most common subtypes separately (Figure 2—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