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.

Directionality in the evolution of influenza A haemagglutinin

“…A similar approach has been suggested earlier by Chen et al (2004) who have detected the majority of known as well as many previously unknown amino acid substitutions that are likely to have arisen in HIV as a response to drug therapy. Their approach was later formalized within the ML framework by Seoighe et al (2007). In this paper, we provide a characterization of the fitness landscape of influenza A HA.…”

Primary Drug Resistance in South Africa: Data from 10 Years of Surveys

“…Eight of these published datasets [34][35][36][37][38][39][40][41] contained sequences derived from HIV-1-infected, ART-naive individuals. Additional HIV-1 pol sequences 42 amplified from untreated patients were retrieved from GenBank and included in the analysis.…”

Evolutionary Biology and Drug Development

“…Drug treatments add to the naturally occurring selective pressures and codon sites that code for resistant mutations are frequently evolving more rapidly than others. A good example of this is a study of serially sampled reverse transcriptase coding sequences isolated from a group of HIV-1 subtype C-infected women before and after single-dose nevirapine (Seoighe et al, 2007). Nevirapine is a standard therapy for preventing mother-to-child transmission.…”