title: A model of directional selection applied to the evolution of drug resistance in HIV-1.
abstract: Understanding how pathogens acquire resistance to drugs is important for the design of treatment strategies, particularly for rapidly evolving viruses such as HIV-1. Drug treatment can exert strong selective pressures and sites within targeted genes that confer resistance frequently evolve far more rapidly than the neutral rate. Rapid evolution at sites that confer resistance to drugs can be used to help elucidate the mechanisms of evolution of drug resistance and to discover or corroborate novel resistance mutations. We have implemented standard maximum likelihood methods that are used to detect diversifying selection and adapted them for use with serially sampled reverse transcriptase (RT) coding sequences isolated from a group of 300 HIV-1 subtype C-infected women before and after single-dose nevirapine (sdNVP) to prevent mother-to-child transmission. We have also extended the standard models of codon evolution for application to the detection of directional selection. Through simulation, we show that the directional selection model can provide a substantial improvement in sensitivity over models of diversifying selection. Five of the sites within the RT gene that are known to harbor mutations that confer resistance to nevirapine (NVP) strongly supported the directional selection model. There was no evidence that other mutations that are known to confer NVP resistance were selected in this cohort. The directional selection model, applied to serially sampled sequences, also had more power than the diversifying selection model to detect selection resulting from factors other than drug resistance. Because inference of selection from serial samples is unlikely to be adversely affected by recombination, the methods we describe may have general applicability to the analysis of positive selection affecting recombining coding sequences when serially sampled data are available.
authors.affiliation: Computational Biology Group, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa. cathal.seoighe@uct.ac.za
authors.forename: Cathal
authors.initials: C
authors.lastname: Seoighe
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Ketwaroo
authors.forename: Visva
authors.initials: V
authors.lastname: Pillay
authors.forename: Konrad
authors.initials: K
authors.lastname: Scheffler
authors.forename: Natasha
authors.initials: N
authors.lastname: Wood
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffet
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Neil
authors.initials: N
authors.lastname: Martinson
authors.forename: James
authors.initials: J
authors.lastname: McIntyre
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D003062:Codon / Q000235:genetics; D003198:Computer Simulation; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D019829:Nevirapine / Q000494:pharmacology / Q000627:therapeutic use; D011247:Pregnancy; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D019380:Anti-HIV Agents; D003062:Codon; D019829:Nevirapine