Modeling HIV-1 drug resistance as episodic directional selection

Abstract

The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

Figure 1. The maximum-likelihood phylogeny for the protease dataset.

Foreground branches are marked in red. All terminal foreground branches lead to sequences obtained from patients who had been receiving antiretroviral therapy. See text for details of how we determined which internal branches were assigned to foreground. MEDS and EDEPS allow the presence of a directional component along the foreground branches where antiretroviral therapy exerts selective pressure.