Virus-Like Particles Displaying Trimeric Simian Immunodeficiency Virus (SIV) Envelope gp160 Enhance the Breadth of DNA/Modified Vaccinia Virus Ankara SIV Vaccine-Induced Antibody Responses in Rhesus Macaques

• Type of Material: Article
• Authors: S. Iyer, Emory University; Sailaja Gangadhara, Emory University; Blandine Victor, Emory University; Xiaoying Shen, Duke University; Xuemin Chen, Emory University; Rafiq Nabi, Louisiana State University; Sudhir Kasturi, Emory University; Michael J. Sabula, Emory University; Celia C. Labranche, Duke University; Pradeep Jagadeesh Reddy, Emory University; Georgia D. Tomaras, Duke University; David C. Montefiori, Duke University; Bernard Moss, National Institutes of Health; Paul Spearman, Emory University; Bali Pulendran, Emory University; Pamela A. Kozlowski, Louisiana State University; Rama Amara, Emory University
• Language: English
• Date: 2016-10-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01163-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 19
• Start Page: 8842
• End Page: 8854
• Grant/Funding Information: This study was supported in part by NIH grants PO1 AI088575 to R.R.A., P51 OD011132 to the Yerkes National Primate Research Center, P30 AI50409 to the Emory Center for AIDS Research, and HHSN27201100016C to D.C.M.; This work, including the efforts of Rama Rao Amara, was funded by National Institute of Allergy and Infectious Diseases (NIAID) (P01 AI088575).; Partial support was also provided by the Division of Intramural Research, NIAID, NIH.
• Keywords: Virology; Life Sciences & Biomedicine; IMMUNOGENICITY; Science & Technology; HIV VACCINE; SIVMAC251; DNA/MVA VACCINE; PROTECTION; IMMUNITY; DENDRITIC CELLS; T-CELL RESPONSES; EFFICACY; MUCOSAL CHALLENGE
• Research Categories: Biology, Virology; Health Sciences, Immunology

Abstract

The encouraging results of the RV144 vaccine trial have spurred interest in poxvirus prime-protein boost human immunodeficiency virus (HIV) vaccine modalities as a strategy to induce protective immunity. Because vaccine-induced protective immunity is critically determined by HIV envelope (Env) conformation, significant efforts are directed toward generating soluble trimeric Env immunogens that assume native structures. Using the simian immunodeficiency virus (SIV)-macaque model, we tested the immunogenicity and efficacy of sequential immunizations withDNA(D), modified vaccinia virus Ankara (MVA) (M), and protein immunogens, all expressing virus-like particles (VLPs) displaying membrane-anchored trimeric Env. A single VLP protein boost displaying trimeric gp160 adjuvanted with nanoparticle-encapsulated Toll-like receptor 4/7/8 (TLR4/7/8) agonists, administered 44 weeks after the secondMVA immunization, induced up to a 3-fold increase in Env-specific IgG binding titers in serum and mucosa. Importantly, the VLP protein boost increased binding antibody against scaffolded V1V2, antibody-dependent phagocytic activity against VLP-coated beads, and antibody breadth and neutralizing antibody titers against homologous and heterologous tier 1 SIVs. Following 5 weekly intrarectal SIVmac251 challenges, two of sevenDNA/MVAand VLP (DM+VLP)-vaccinated animals were completely protected compared to productive infection in all seven DM-vaccinated animals. Vaccinated animals demonstrated stronger acute viral pulldown than controls, but a trend for higher acute viremia was observed in the DM+VLP group, likely due to a slower recall of Gag-specific CD8 T cells. Our findings support immunization with VLPs containing trimeric Env as a strategy to augment protective antibody but underscore the need for optimal engagement of CD8 T cells to achieve robust early viral control.