Toward an Effective HIV-1 Vaccine: Multivalent Nanoparticle Immunogens and Public Antibodies

Abstract

Despite decades of research, there currently are no licensed HIV-1 vaccines. However, interrogation of antibody repertoires in HIV-1+ individuals have identified antibodies capable of neutralizing a broad variety of globally circulating HIV-1 viruses. The target of these neutralizing antibodies is the envelope glycoprotein (Env) expressed on the surface of the virus. Env-based vaccines have largely fallen short of an efficacious vaccine, in part due to the diversity of circulating viruses. Nevertheless, a variety of technologies have been developed to overcome these shortcomings. This dissertation provides reports of two complementary but distinct methodologies that have the potential to lead to an effective HIV-1 vaccine. In interrogating the repertoire of HIV-1+ individuals, we identified antibodies shared among individuals with sequence features that modulate antigen recognition and function, including neutralization. These findings provide motivation to design vaccines that can elicit population-level antibody responses. In developing nanoparticle immunogens, we harness and display inherent HIV-1 diversity to the immune system and show that mosaic nanoparticles and single-antigen cocktails can elicit broad responses in guinea pigs. Taken together, we believe there is utility in testing nanoparticle immunogens capable of eliciting population-level antibody responses.