Antiviral drug resistance as an adaptive process

Abstract

Antiviral drug resistance is a matter of great clinical importance that, historically, has been investigated mostly from a virological perspective. Although the proximate mechanisms of resistance can be readily uncovered using these methods, larger evolutionary trends often remain elusive. Recent interest by population geneticists in studies of antiviral resistance has spurred new metrics for evaluating mutation and recombination rates, demographic histories of transmission and compartmentalization, and selective forces incurred during viral adaptation to antiviral drug treatment. We present up-to-date summaries on antiviral resistance for a range of drugs and viral types, and review recent advances for studying their evolutionary histories. We conclude that information imparted by demographic and selective histories, as revealed through population genomic inference, is integral to assessing the evolution of antiviral resistance as it pertains to human health.

Keywords: antiviral resistance; compensatory mutation; cost of adaptation; fluctuating selection; genetic barrier; mutagenesis.

Figure 1.

Depictions of viral replication and protein synthesis. Representative replication mechanisms for DNA viruses HSV and HCMV, RNA viruses HCV and IAV, lentivirus HIV, and HBV. Bright blue strands represent viral DNA, green strands represent viral RNA, pink shapes represent virally produced enzymes, and purple shapes represent host-produced enzymes. When necessary, positive and negative-sense RNAs are designated with (+) and (−), respectively; note that only positive-sense RNA can be directly translated into proteins. Arrows indicate transcription, translation, replication, or integration activity, as denoted either by descriptive grey text or by the nearest enzyme. Bold, italicized text indicates drug classes for which known resistance mutations occur; the nearest enzyme (or replicative process) indicates the target of that drug class.

Figure 2.

Resistance and associated fitness costs in drug absence. A meta-analysis of antiviral resistance mutations, particularly the level of resistance conferred in the presence of a drug, and viral fitness in the absence of drug. The figure is composed of metadata from studies that reported both (i) the IC₅₀ ratio between wild-type and resistant viral strains measured with a common (non-experimental) antiviral, and (ii) the replication rates of both of those strains in a drug-free environment. A total of 76 observations were recorded from 18 studies involving five viral types (all of those reviewed here except HSV, for which there was no data available fitting the above criteria). Resistance mutations to the following drugs are included: oseltamivir (H1N1), ganciclovir (HCMV), lamivudine (HBV), boceprevir (HCV), telaprevir (HCV), raltegravir (HIV), elvitegravir (HIV), L-708906 (HIV), L-731988 (HIV), lamivudine (HIV), adefovir, (HIV), efavirenz, (HIV), and rilpivirine (HIV). However, neither drug nor target was a significant predictor of fitness costs according to a generalized linear model (P > 0.05). Data were sourced from Cihlar et al. (1998), Hazuda et al. (2000), Naeger et al. (2001), Ives et al. (2002), Chou et al. (2003), Brunelle (2005), Springer et al. (2005), Chou et al. (2007), Kobayashi et al. (2008), Baz et al. (2010), Martin et al. (2010), Abed et al. (2011), Shimakami et al. (2011), Wong et al. (2012), Jiang et al. (2013), Mesplède et al. (2013), Zhang 2013), Hu and Kuritzkes (2014) and can be found in the Supplementary Table.