Host-Pathogen Coevolution and the Emergence of Broadly Neutralizing Antibodies in Chronic Infections

The vertebrate adaptive immune system provides a flexible and diverse set of molecules to neutralize pathogens. Yet, viruses such as HIV can cause chronic infections by evolving as quickly as the adaptive immune system, forming an evolutionary arms race. Here we introduce a mathematical framework to study the coevolutionary dynamics between antibodies and antigens within a host. We focus on changes in the binding interactions between the antibody and antigen populations, which result from the underlying stochastic evolution of genotype frequencies driven by mutation, selection, and drift. We identify the critical viral and immune parameters that determine the distribution of antibody-antigen binding affinities. We also identify definitive signatures of coevolution that measure the reciprocal response between antibodies and viruses, and we introduce experimentally measurable quantities that quantify the extent of adaptation during continual coevolution of the two opposing populations. Using this analytical framework, we infer rates of viral and immune adaptation based on time-shifted neutralization assays in two HIV-infected patients. Finally, we analyze competition between clonal lineages of antibodies and characterize the fate of a given lineage in terms of the state of the antibody and viral populations. In particular, we derive the conditions that favor the emergence of broadly neutralizing antibodies, which may have relevance to vaccine design against HIV.
Author Summary We normally think of evolution occurring in a population of organisms, in response to their external environment. Rapid evolution of cellular populations also occurs within our bodies when the adaptive immune system works to eliminate infections. Some viruses, such as HIV, are able to evolve as quickly as our immune response, resulting in a chronic infection with both viral and immune populations perpetually adapting. Here we develop a mathematical description of this coevolutionary process, discover key parameters that govern the distribution of interactions between the two populations, introduce principled measures of adaptation, and analyze the conditions under which highly potent broadly neutralizing antibodies will emerge and dominate the immune response.