Exploring the Complexity of the HIV-1 Fitness Landscape

Although fitness landscapes are central to evolutionary theory, so far no biologically realistic examples for large-scale fitness landscapes have been described. Most currently available biological examples are restricted to very few loci or alleles and therefore do not capture the high dimensionality characteristic of real fitness landscapes. Here we analyze large-scale fitness landscapes that are based on predictive models for in vitro replicative fitness of HIV-1. We find that these landscapes are characterized by large correlation lengths, considerable neutrality, and high ruggedness and that these properties depend only weakly on whether fitness is measured in the absence or presence of different antiretrovirals. Accordingly, adaptive processes on these landscapes depend sensitively on the initial conditions. While the relative extent to which mutations affect fitness on their own (main effects) or in combination with other mutations (epistasis) is a strong determinant of these properties, the fitness landscape of HIV-1 is considerably less rugged, less neutral, and more correlated than expected from the distribution of main effects and epistatic interactions alone. Overall this study confirms theoretical conjectures about the complexity of biological fitness landscapes and the importance of the high dimensionality of the genetic space in which adaptation takes place. Author Summary: Evolutionary adaptation can be understood as populations moving uphill on landscapes, in which height corresponds to evolutionary fitness. Although such fitness landscapes are central to evolutionary theory, there is currently a lack of biologically realistic examples. Here we analyze large-scale fitness landscapes derived from in vitro fitness measurements of HIV-1. We find that these landscapes are very rugged and that, accordingly, adaptive processes on these landscapes depend sensitively on the initial conditions. Moreover, the landscapes contain large networks along which fitness changes only minimally. While the relative extent to which mutations affect fitness on their own or in combination with other mutations is a strong determinant of these properties, the fitness landscape of HIV-1 is considerably less rugged than expected from the individual and pair-wise effects of mutations. Overall this study confirms theoretical conjectures about the complexity of biological fitness landscapes and the importance of the high dimensionality of the genetic space in which adaptation takes place.