The HIV envelope protein complex is the only exposed target on the virus for binding by neutralizing antibodies, which is the first step in successfully blocking HIV infection. Here we show the first demonstration of B cell follicle (blue) targeting of HIV envelope proteins (red) within mouse draining lymph nodes upon immunization with a fully defined synthetic protein nanoparticle platform. The trafficking profile of this vaccine platform allows for sustained antigen exposure within active germinal centers (green), which are the sites of B cell maturation and potent antibody production required for long-term protection against the virus. This is a highly translatable nanoparticle platform that has the potential to be the basis for an eventual prophylactic HIV vaccine.