title: More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1.
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.
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.
authors.forename: Alison F
authors.initials: AF
authors.lastname: Feder
authors.affiliation: Department of Medicine, Stanford University, Stanford, United States.
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.affiliation: Department of Statistics, Stanford University, Stanford, United States.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Holmes
authors.affiliation: Department of Medicine, Stanford University, Stanford, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Petrov
authors.affiliation: Department of Biology, Stanford University, Stanford, United States.|Department of Biology, San Francisco State University, San Francisco, United States.
authors.forename: Pleuni S
authors.initials: PS
authors.lastname: Pennings
mesh_terms: D000220:Adaptation, Biological; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D059645:Mutation Rate; D012641:Selection, Genetic
chemical_list: D019380:Anti-HIV Agents
keywords: HIV; drug resistance; evolutionary biology; evolutionary dynamics; genomics; soft sweeps; within-host evolutionary