Article

Modeling HIV-1 Drug Resistance as Episodic Directional Selection

Imperial College London, United Kingdom
PLoS Computational Biology (Impact Factor: 4.83). 05/2012; 8(5):e1002507. DOI: 10.1371/journal.pcbi.1002507
Source: PubMed

ABSTRACT Author Summary
When exposed to treatment, HIV-1 and other rapidly evolving viruses have the capacity to acquire drug resistance mutations (DRAMs), which limit the efficacy of antivirals. There are a number of experimentally well characterized HIV-1 DRAMs, but many mutations whose roles are not fully understood have also been reported. In this manuscript we construct evolutionary models that identify the locations and targets of mutations conferring resistance to antiretrovirals from viral sequences sampled from treated and untreated individuals. While the evolution of drug resistance is a classic example of natural selection, existing analyses fail to detect the majority of DRAMs. We show that, in order to identify resistance mutations from sequence data, it is necessary to recognize that in this case natural selection is both episodic (it only operates when the virus is exposed to the drugs) and directional (only mutations to a particular amino-acid confer resistance while allowing the virus to continue replicating). The new class of models that allow for the episodic and directional nature of adaptive evolution performs very well at recovering known DRAMs, can be useful at identifying unknown resistance-associated mutations, and is generally applicable to a variety of biological scenarios where similar selective forces are at play.

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    • "Methods that quantify the strength and type of natural selection by estimating the ratio of nonsynonymous to synonymous substitution (!) using phylogenetic codon-substitution models, pioneered by Muse and Gaut (1994) and Goldman and Yang (1994), have proven particularly popular and useful. In the context of infectious diseases (see Aguileta et al. 2009 for a review), these models have been used successfully to study transmission (Jonges et al. 2011), zoonosis (Demogines et al. 2012), the evolution of drug resistance (Stanhope et al. 2008; Hill et al. 2009; Murrell, De Oliveira, et al. 2012), escape from host immune response (Frost et al. 2005; Cento et al. 2013), the development of pathogenicity and virulence (Brault et al. 2007), emergence of new strains (Schuh et al. 2014), and evolutionary arms-races between viruses and host antiviral defenses (Duggal et al. 2011; Daugherty et al. 2014). A key feature of natural selection is its variability. "
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