An Evolutionary Model-Based Algorithm for Accurate Phylogenetic Breakpoint Mapping and Subtype Prediction in HIV-1

Abstract

Genetically diverse pathogens (such as Human Immunodeficiency virus type 1, HIV-1) are frequently stratified into phylogenetically or immunologically defined subtypes for classification purposes. Computational identification of such subtypes is helpful in surveillance, epidemiological analysis and detection of novel variants, e.g., circulating recombinant forms in HIV-1. A number of conceptually and technically different techniques have been proposed for determining the subtype of a query sequence, but there is not a universally optimal approach. We present a model-based phylogenetic method for automatically subtyping an HIV-1 (or other viral or bacterial) sequence, mapping the location of breakpoints and assigning parental sequences in recombinant strains as well as computing confidence levels for the inferred quantities. Our Subtype Classification Using Evolutionary ALgorithms (SCUEAL) procedure is shown to perform very well in a variety of simulation scenarios, runs in parallel when multiple sequences are being screened, and matches or exceeds the performance of existing approaches on typical empirical cases. We applied SCUEAL to all available polymerase (pol) sequences from two large databases, the Stanford Drug Resistance database and the UK HIV Drug Resistance Database. Comparing with subtypes which had previously been assigned revealed that a minor but substantial (≈5%) fraction of pure subtype sequences may in fact be within- or inter-subtype recombinants. A free implementation of SCUEAL is provided as a module for the HyPhy package and the Datamonkey web server. Our method is especially useful when an accurate automatic classification of an unknown strain is desired, and is positioned to complement and extend faster but less accurate methods. Given the increasingly frequent use of HIV subtype information in studies focusing on the effect of subtype on treatment, clinical outcome, pathogenicity and vaccine design, the importance of accurate, robust and extensible subtyping procedures is clear. There are nine different subtypes of the main group of HIV-1, each originating as a distinct subepidemic of HIV-1. The distribution of subtypes is often unique to a given geographic region of the world and constitutes a useful epidemiological and surveillance resource. The effects of viral subtype on disease progression, treatment outcome and vaccine design are being actively researched, and the importance of accurate subtyping procedures is clear. In HIV-1, subtype assignment is complicated by frequent recombination among co-circulating strains, creating new genetic mosaics or recombinant forms: 43 have been characterized to date, and many more likely exist. We present an automated phylogenetic method (SCUEAL) to accurately characterize both simple and complex HIV-1 mosaics. Using computer simulations and biological data we demonstrate that SCUEAL performs very well under various conditions, especially when some of the existing classification procedures fail. Furthermore, we show that a small, but noticeable proportion of subtype characterization stored in public databases may be incomplete or incorrect. The computational technique introduced here should provide a much more accurate characterization of HIV-1 strains, especially novel recombinants, and lead to new insights into molecular history, epidemiology and geographical distribution of the virus.