PROJECT SUMMARY/ABSTRACT Stabilized HIV-1 envelope gp140 trimers such as BG505 SOSIP provide a viable platform to elicit protective neutralizing antibodies that can be improved upon through various approaches to induce heterologous neutralizing breadth. BG505 SOSIP trimer immunization elicits protective neutralizing antibodies in rhesus macaques and is now being tested in several phase I clinical trials, including HVTN 137. Here we will perform in-depth studies to determine how antibodies that neutralize only the autologous virus and those that also have activity against heterologous viral variants developed in parallel during BG505 SOSIP immunization of rhesus macaques using cryopreserved samples. We will then track the antibody germline precursors for these neutralizing antibodies in other immunized rhesus macaques that share the allele to understand why they sometimes failed to develop these activities. We will also compare the targets of the neutralizing antibody responses in BG505 SOSIP immunized human subjects to those recognized in the rhesus macaque model. The HVTN 137 trial is also administering BG505 SOSIP with different adjuvants and we will investigate how these impact neutralizing antibody specificities in the human volunteers. Finally, we will isolate neutralizing monoclonal antibodies from selected BG505 SOSIP immunized rhesus macaques and human subjects to compare the structural and biophysical properties of antigen recognition. These extensive pre-clinical and clinical resources combined with our multidisciplinary expertise provides a novel setting in which to address barriers that impede the development of effective HIV vaccination strategies. If successful, these studies will illuminate new strategies to improve upon HIV-1 trimer envelope immunogens and adjuvants.