During the course of an individual's infection with Human Immunodeficiency Virus (HIV), the virus population consists of a distribution of different variants, produced by mutation and selection. Consequently, the immune system attempts to build a response that is broad enough to handle the diversity of virus strains present. Biological experiments have shown that neutralizing antibodies fail to offer long-term protection because they are primarily strain-specific and lag behind viral evolution. The proposed research presents a thorough investigation of the antibody mediated immune responses against HIV with an emphasis on their neutralizing and non-neutralizing activity. Novel mathematical models of antibody responses following infection with HIV are developed, analyzed using asymptotic analysis, bifurcation analysis and numerical analysis, and validated against biological data in order to quantify the relative importance of biological processes in influencing disease evolution. The investigator aims to discover which factors (host or virus specific) influence the outcome of the infection. The specific goals are in understanding (1) the roles of competition and cross-reactivity between families of neutralizing antibodies in the presence and absence of virus evolution; (2) the necessity of antibodies to neutralize every viral spike; and (3) the role of non-neutralizing antibodies. All these questions will have implications for vaccine development as well as for disease prognosis. The ability of HIV to persist in an infected individual and eventually cause AIDS depends on its avoidance of the immune system. Of the two immune mechanisms present, the cellular response is better understood, while the antibody response is still under investigation. Understanding of how antibodies respond to the virus is crucial for the success of any future vaccine candidate, especially since current therapeutic vaccines focus on inducing both arms of the immune response. The goal of this proposal is to investigate how particular biological interactions can lead to an efficient antibody response during both immunization and natural infection with HIV. Given the difficulty and cost of experimentally examining all of the biological interactions involved, we consider alternative methods for testing new hypotheses. They consist of the development, analysis and validation against biological data of mathematical models, with the goal of providing insight into the dynamics of antibody responses. This knowledge may eventually guide treatment and prevention, and assist in establishing immunological goals for an effective AIDS vaccine. The research aims to promote the advancement of mathematical and biological knowledge, provide an opportunity for interdisciplinary collaboration with researchers in the mathematical and medical communities, and lead to the training of graduate and undergraduate students. The PI plans to incorporate ideas and results from the proposed research into a first year graduate Mathematical Biology course, as well as a summer course directed at undergraduate mathematics majors across Louisiana, and to engage with graduate and undergraduate students to incorporate this research as part of their dissertation and summer research programs.
