Hypothermia Exposes Hidden Epitopes in Influenza A Hemagglutinin and Potentiates the Binding of Neutralizing Antibodies

Abstract

Influenza viruses are an important cause of human morbidity and mortality. Influenza uses hemagglutinin, a trimeric surface protein whose monomers are composed of a head and a stalk domain, for immune evasion and cell entry. As the head domain is under constant antigenic drift, eliciting neutralizing antibodies through vaccination against its evolutionarily more conserved stalk domain is a key goal in the treatment of this infection. It is unknown how temperature affects the formation of hemagglutinin-antibody complexes, particularly with respect to temperatures relevant for the human respiratory tract. Using molecular dynamics simulations and free energy calculations, we determined that bending of hemagglutinin's head domains, an initial step in the process of cell attachment, is present at hypothermia (36 °C), but not at higher temperatures. These conformational changes lead not only to exposure of new epitopes in its stalk domains, but also to enhanced binding of a neutralizing antibody.