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 MedicalCenter (JJP VAMC), Bronx, NY, and a tenured Professor of Medicine at the Icahn School of Medicine at MountSinai. She joined the VA via the Merit Review Entry Program in 1998 and established her research laboratoryinitially at the VA New York Harbor Healthcare System–Manhattan, moving in 2015 to the JJP VAMC. Shereceived an RCS award (10/1/12-9/30/17) and a one-year Cost Extension through 9/30/18, in part for recoveryfrom Superstorm Sandy (10/29/12). Despite the setback from that storm, her lab continues to excel, asevidenced 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 andpathogenesis. This program is also supported by a robust non-VA research program. The Hioe lab isinvestigating the immunogenic and immunopathogenic properties of the HIV envelope (Env), a glycoproteinthat may be targeted by host responses to reduce virus transmissibility and infectivity. In particular, Dr. Hioe'sstudies have focused on harnessing the antiviral potential of anti-HIV Env antibodies beyond theirconventionally measured virus-neutralizing activity. The anti-Env antibodies of interest do not fall into thebroadly and potently neutralizing category but, instead, target immunogenic conserved sites and can begenerated 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 ofdiverse isolates from multiple subtypes. Importantly, V1V2 antibodies have been identified as an immunecorrelate of reduced risk of HIV acquisition in the Thai RV144 HIV vaccine trial, the only phase III clinical trial toshow vaccine-induced protection (albeit short-lived and with a modest efficacy of 31.2%). Antibodies to the V3loop 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 hasdemonstrated the following major findings: 1) Although V1V2 and V3 antibodies display no or poor activity instandard neutralization assays, their neutralizing activity can be enhanced by prolonging the time allowed forvirus-antibody interaction; this is indicative of the highly dynamic nature of HIV Env, which affects V1V2 and V3accessibility 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 V3antibodies is modulated by signal sequence changes. 3) V1V2 and V3 antibodies block the HIV Envcostimulatory activity that enhances CD4 T cell activation and renders the cells more susceptible to infection.This costimulatory activity is dependent on T-cell receptor engagement and antigen-presenting cells (APCs),does not require infectious virus, and can be triggered by monomeric Env with accessible V1V2 and V3,allowing effective blockade by antibodies against these regions. 4) Finally, passive transfer of V1V2 and V3antibodies results in control of HIV infection in the humanized mouse model, similar to that seen in rhesusmacaques challenged with a chimeric SHIV virus. Dr. Hioe has published 32 peer-reviewed research articlesover the past 10 years to report these and other, related studies. She has mentored >30 trainees andparticipated in numerous committees within and outside the VA. She also has been awarded a number ofgrants: In 2017 and 2018, she received an NIH R21 award to study the role of signal sequence in regulatingHIV Env expression and glycosylation, an NIH R01 grant to assess antiviral mechanisms of non-neutralizingantibodies, and a VA Merit Review award to evaluate HIV interaction with antibodies and APCs.
|Effective start/end date||1/04/19 → 31/03/24|
- U.S. Department of Veterans Affairs