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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.

journal_name

Mol Biol Evol

journal_title

Molecular biology and evolution

authors

Seoighe C,Ketwaroo F,Pillay V,Scheffler K,Wood N,Duffet R,Zvelebil M,Martinson N,McIntyre J,Morris L,Hide W

doi

10.1093/molbev/msm021

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

1025-31

issue

4

eissn

0737-4038

issn

1537-1719

pii

msm021

journal_volume

24

pub_type

杂志文章

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