Research Project
10008960
Abstract ? Core C (Primate Studies) This HIVRAD proposal is based on our data that the dimeric IgA1 (dIgA1) form of a neutralizing monoclonal antibody (nmAb) given intrarectally (i.r.) protected most rhesus macaques (RMs) against i.r. clade C simian- human immunodeficiency virus (SHIV-C) challenge; dIgA2 yielded minimal protection, although both dIgA2 and dIgA1 neutralized SHIV-C equally well in vitro. In a 2nd study, intravenous (i.v.) administration of the nmAb as IgG1 and i.r. as dIgA2 gave 100% protection, whereas the same nmAbs given alone gave no or low protection. A better understanding of this synergy is the aim of Project 1. Project 2 will test systemically administered monoclonal IgGs ? both neutralizing and non-neutralizing and inducible by current immunogens ? and/or mucosally delivered dIgAs for efficacy against SHIV-C alone or in combination. Project 3 will test a novel lymph node (LN)-targeting technology to induce immune responses at the mucosal level, the portal of virus entry. The overall objective of Core C is to provide experimental RMs and support services (animal care, veterinary care, and surgical procedures) to achieve the goals of all three Projects. Core C will identify suitable RMs from the specific pathogen-free (SPF) colonies at the Southwest National Primate Research Center (SNPRC) and will perform MHC class I (Mamu A*01, B*08, B*17) genotyping to provide suitable RMs. Core C will perform i.r. titrations of a new tier 2 SHIV-C stock (SHIV-1157ipd3N4) to determine the dose to challenge RMs by single high-dose exposure (Project 2) and by repeated low-dose exposures (Project 3). Core C will carry out passive administration of mAbs by the appropriate route to RMs for Project 1 and 2; vaccinate (prime and boost) the RMs with novel LN-targeting immunogens for Project 3 and also perform the following tasks: Project 1: exposure of fluorescently labeled virus to mucosa and collection of the biopsies and/or mucosal fluids for ex vivo analysis; Project 2: single high-dose i.r. SHIV-C challenge, followed by periodic collection of required specimens (blood and/or mucosal specimens) for assessment of plasma viremia and antibody levels; Project 3: periodic collection of specimens (blood and/or mucosal specimens) for assessment of vaccine immunogenicity, i.r. repeated low-dose virus challenges, and periodic collection of post-challenge specimens (blood and/or mucosal specimens) for assessment of vaccine efficacy; Core D: coordinate and manage the transport of RMs between SNPRC and the Research Imaging Institute (Core D). Using radiolabeled mAbs and virus, Core D will perform PET scans to follow virus- antibody interactions (Project 1); trafficking of radiolabeled immunogens to mucosal LNs will be investigated for Project 3. RM specimens will be provided to Projects and/or Core B for analysis. Core C will also perform necropsies.
