Date Published: September 14, 2004
Publisher: Public Library of Science
Author(s): Eddie C Holmes
Abstract: The ongoing battle between hosts and pathogens has long been of interest to evolutionary biologists.
Partial Text: The ongoing battle between hosts and pathogens has long been of interest to evolutionary biologists. Because hosts and pathogens act as environments for each other, their intertwined struggle for existence is both continual and rapid. At the molecular level, this cycle of environmental change and evolutionary response means that mutations are continually being tried out by natural selection. It is therefore little wonder that the host and pathogen genes that control infection and immunity frequently show high levels of genetic diversity and present some of the best examples of positive selection (adaptive evolution) reported to date (Yang and Bielawski 2000). In particular, rates of nonsynonymous substitution per site (resulting in an amino acid change; dN) often greatly exceed those of synonymous substitution per site (silent change; dS), as expected if most mutations are fixed because they increase fitness (Figure 1).
The genes involved in innate immunity have recently come under the molecular evolutionists’ gaze. One important group are the defensins, a large class of short antimicrobial peptides that constitute an effective immune response team in organisms as diverse as plants and primates (Boman 1995). Because defensins are cationic (positively charged), they are able to interact with negatively charged molecules on the surface of microbes and permeate their membranes. Sequence analyses of defensins and similar antimicrobial peptides have revealed the telltale signatures of positive selection, with dN greater than dS in many comparisons (Hughes 1999; Duda et al. 2002; Maxwell et al. 2003). Other genes of the innate immune system also seem to be subject to powerful positive selection. One dramatic example described in this issue of PLoS Biology is the APOBEC3G gene of primates (Sawyer et al. 2004). This case is especially striking because rather than killing pathogens through protein or cellular interactions, like most immune genes, APOBEC3G works by manipulating the genome sequence of the invading microbe.
The high mutation rates of RNA viruses mean that adaptively useful genetic variation is produced frequently. The rub, however, is that fitness-enhancing mutations are a small minority, and the preponderance of deleterious mutations means that RNA viruses live on the edge of survival (Domingo 2000). By increasing the rate at which deleterious mutations appear, APOBEC3G pushes viruses over this edge, causing a form of ‘lethal mutagenesis’ that results in their destruction; the rate of mutation becomes so high that no genome can reproduce itself faithfully, and the population crashes. Intriguingly, researchers designing new antiviral drugs have also begun to realise that forcing viruses into this sort of ‘error catastrophe’ might be an effective way to treat them (Figure 2). There are a growing number of studies in which mutagens, such as ribavirin and 5-fluorouracil, are applied to viral infections in vitro and in vivo, including HIV, in the hope that these will induce so many deleterious mutations that the virus suffers an error catastrophe and is cleared (Loeb et al. 1999; Sierra et al. 2000; Crotty et al. 2001; Ruiz-Jarabo et al. 2003). The results produced to date are highly encouraging, particularly when these error-inducing drugs are combined with more conventional treatment strategies that aim to reduce the rate of viral replication (Pariente et al. 2001). The discovery that a natural antiviral agent, APOBEC3G, probably works in much the same way should provide even more encouragement.