This application is to request a renewal of the BLR&D Research Career Scientist (RCS) award for Dr. Catarina Hioe. Dr. Hioe is a Research Health Specialist (GS13 Step 8) at the James J. Peters VA Medical Center (JJP VAMC), Bronx, NY, and a tenured Professor of Medicine at the Icahn School of Medicine at Mount Sinai. She joined the VA via the Merit Review Entry Program in 1998 and established her research laboratory initially at the VA New York Harbor Healthcare System–Manhattan, moving in 2015 to the JJP VAMC. She received an RCS award (10/1/12-9/30/17) and a one-year Cost Extension through 9/30/18, in part for recovery from Superstorm Sandy (10/29/12). Despite the setback from that storm, her lab continues to excel, as evidenced by an array of accomplishments in each of the key measures that are highlighted in this application. Over the past 20 years, Dr. Hioe has built a VA research program to study HIV immunology and pathogenesis. This program is also supported by a robust non-VA research program. The Hioe lab is investigating the immunogenic and immunopathogenic properties of the HIV envelope (Env), a glycoprotein that may be targeted by host responses to reduce virus transmissibility and infectivity. In particular, Dr. Hioe's studies have focused on harnessing the antiviral potential of anti-HIV Env antibodies beyond their conventionally measured virus-neutralizing activity. The anti-Env antibodies of interest do not fall into the broadly and potently neutralizing category but, instead, target immunogenic conserved sites and can be generated by the vast majority of individuals. Specifically, these antibodies target the variable loops 1, 2, and 3 (V1V2 and V3), which form the apex of an HIV Env spike. Although these loops have variable amino acids, they maintain conserved structures that are recognized by cross-reactive antibodies able to bind HIV Env of diverse isolates from multiple subtypes. Importantly, V1V2 antibodies have been identified as an immune correlate of reduced risk of HIV acquisition in the Thai RV144 HIV vaccine trial, the only phase III clinical trial to show vaccine-induced protection (albeit short-lived and with a modest efficacy of 31.2%). Antibodies to the V3 loop also correlated with lower rates of HIV acquisition in a subset of RV144 vaccine recipients. As a result of their research into how anti-V1V2 and -V3 antibodies confer this protection, the Hioe lab has demonstrated the following major findings: 1) Although V1V2 and V3 antibodies display no or poor activity in standard neutralization assays, their neutralizing activity can be enhanced by prolonging the time allowed for virus-antibody interaction; this is indicative of the highly dynamic nature of HIV Env, which affects V1V2 and V3 accessibility to antibodies. 2) V1V2 and V3 exposure is also regulated by N-glycans that shroud the virus Env; glycan composition is dictated in part by Env signal sequence. Hence, virus susceptibility to V1V2 and V3 antibodies is m...