Therapeutic vaccination of SIV-infected, ART-treated infant rhesus macaques using Ad48/MVA in combination with TLR-7 stimulation

• Type of Material: Article
• Authors: Katherine M. Bricker, Emory University; Veronica Obregon-Perko, Emory University; Ferzan Uddin, Emory University; Brianna Williams, Emory University; Emilie A. Uffman, Duke University; Carolina Garrido, Duke University; Genevieve G. Fouda, Duke University; Romas Geleziunas, Gilead Sciences Inc; Merlin Robb, Walter Reed Army Institute of Research; Nelson Michael, Walter Reed Army Institute of Research; Dan H. Barouch, Harvard Medical School; Ann Chahroudi, Emory University
• Language: English
• Date: 2020-10-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008954
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 16
• Issue: 10
• Start Page: e1008954
• End Page: e1008954
• Grant/Funding Information: This work was supported in part with federal funds from the U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov/) R01 AI133706 to AC and P01 AI131276 to AC and GGF. Research was also supported by YNPRC (P51 OD011132), the Pediatric/Winship Flow Cytometry Core (P30 CA138292), and the Center for AIDS Research at Emory University (P30 AI050409). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript and the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: HIV-1; Life Sciences & Biomedicine; Science & Technology; MODELS; REPLICATION; Microbiology; RESERVOIR; CELL RESPONSES; Virology; VECTORS; Parasitology
• Research Categories: Biology, Parasitology; Biology, Virology; Biology, Cell; Biology, Microbiology

Abstract

Globally, 1.8 million children are living with HIV-1. While antiretroviral therapy (ART) has improved disease outcomes, it does not eliminate the latent HIV-1 reservoir. Interventions to delay or prevent viral rebound in the absence of ART would be highly beneficial for HIV-1infected children who now must remain on daily ART throughout their lifespan. Here, we evaluated therapeutic Ad48-SIV prime, MVA-SIV boost immunization in combination with the TLR-7 agonist GS-986 in rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen beginning 4 weeks after infection. We hypothesized immunization would enhance SIV-specific T cell responses during ART-mediated suppression of viremia. Compared to controls, vaccinated infants had greater magnitude SIV-specific T cell responses (mean of 3475 vs 69 IFN-γ spot forming cells (SFC) per 106 PBMCs, respectively, P = 0.01) with enhanced breadth of epitope recognition and increased CD8+ and CD4+ T cell polyfunctionality (P = 0.004 and P = 0.005, respectively). Additionally, SIV-specific gp120 antibodies against challenge and vaccine virus strains were significantly elevated following MVA boost (P = 0.02 and P < 0.001, respectively). GS-986 led to expected immune stimulation demonstrated by activation of monocytes and T cells 24 hours post-dose. Despite the vaccine-induced immune responses, levels of SIV DNA in peripheral and lymph node CD4+ T cells were not significantly different from controls and a similar time to viral rebound and viral load set point were observed following ART interruption in both groups. We demonstrate infant RMs mount a robust immunological response to this immunization, but vaccination alone was not sufficient to impact viral reservoir size or modulate rebound dynamics following ART release. Our findings hold promise for therapeutic vaccination as a part of a combination cure approach in children and highlight the importance of a pediatric model to evaluate HIV-1 cure interventions in this unique setting of immune development.