Rapid adversarial co-evolution of viruses and cellular restriction factors

Since the discovery of viruses over a century ago, virologists have recognized that host genetics plays a major role in viral tropism and the distribution of viruses in nature. Traditionally, studies of tropism have centered on identification of cellular factors required for viral replication, such as cell-surface entry receptors. However, over the past 20 years, there has been a steady increase in the identification and characterization of restriction factors (RFs), here defined as dominant cellular factors that have evolved specifically to interfere with viral replication. Genetic studies suggest that restriction factors impose significant barriers to interspecies movement of viruses and are therefore critical determinants of viral tropism. Furthermore, the scope of the ever-expanding list of restriction factors, and the variety of antiviral mechanisms they represent, testifies to the extraordinary impact viruses have had on organismal evolution-an impact hitherto underappreciated by evolutionary biologists and virologists alike. Recent studies of RF-encoding genes that combine molecular evolutionary analysis with functional assays illustrate the potential for asking questions about virus-host interactions as they play out in natural populations and across evolutionary timescales. Most notably, it has become common to apply tests of positive selection to RF genes and couple these analyses with virological assays, to reveal evidence for antagonistic virus-host co-evolution. Herein, I summarize recent work on the evolutionary genetics of mammalian RFs, particularly those of humans, non-human primates, and model organisms, and how RFs can reveal the influence of virus-host interactions on organismal evolution. Because intensive investigation of RF evolution is fairly new (and because there is still much to learn), the discussion is organized around five broad, outstanding questions that will need to be answered before we can fully appreciate the evolutionary biology of restriction.