Structural Biology and the Design of Effective Vaccines for HIV-1 and Other Viruses

Abstract

Structural biology provides a wealth of information about the three-dimensional organization and chemical makeup of proteins. An understanding of atomic-level structure offers enormous potential to design rationally proteins that stimulate specific immune responses. Yet current vaccine development efforts makes little use of structural information. At the Vaccine Research Center, a major goal is to apply structural techniques to vaccine design for challenging pathogens, that include human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses such as influenza, Ebola, and respiratory syncytial viruses. Our three-part strategy involves 1.) the definition of the functional viral spike at the atomic level 2.) achieving a structural understanding of how neutralizing antibodies recognize the spike, and 3.) rational development of proteins that can elicit a specific antibody response. Overall, our strategy aims to incorporate information about viral spike-antibody interactions, to assimilate immunogenic feedback, and to leverage recent advances in immunofocus-ing and computational biology. For an elusive pathogen such as HIV-1, whether such a strategy will succeed depends both on the existence of sites of envelope (Env) vulnerability susceptible to neutralizing antibody and on the ability of the human immune system to generate high titers of such antibodies. With HIV-1, the atomic-level definition of one such vulnerable site [1] and the discovery of individuals with broadly neutralizing sera that target this site [2] bodes well for our informatics-based approach. With Ebola and influenza viruses, structures of functional viral spikes have been determined [3, 4], and sites of antibody vulnerability and elicitation of appropriate antibodies are under investigation. With respiratory syncytial virus, structures of closely related spikes have been determined [5], and issues center on the elicitation of antibodies that defuse rather than exacerbate disease.