Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses

• Type of Material: Article
• Authors: Stella J Berendam, Duke University; Tiffany M Styles, Emory University; Papa K Morgan-Asiedu, Duke University; DeAnna Tenney, Duke University; Amit Kumar, Duke University; Veronica Obregon-Perko, Emory University; Katharine J Bar, University of Pennsylvania; Kevin O Saunders, Duke University; Sampa Santra, Beth Israel Deaconess Medical Center; Kristina De Paris, University of North Carolina; Georgia D Tomaras, Duke University; Ann Chahroudi, Emory University; Sallie R Permar, Duke University; Rama Amara, Emory University; Genevieve G Fouda, Duke University
• Language: English
• Date: 2021-02-01
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 American Society for Microbiology.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01667-20
• Title of Journal or Parent Work: JOURNAL OF VIROLOGY
• Volume: 95
• Issue: 3
• Grant/Funding Information: This study was supported by the National Institutes of Health under awards 5P01 AI131276 to S.R.P. and U19AI109633 to R.R.A.; This project was funded in part by the Yerkes National Primate Research Center (grant ORIP/OD P51OD011132), which is supported by the NIH, Office of Research Infrastructure Programs.
• Keywords: SHIV; VIREMIA; Life Sciences & Biomedicine; DRUG-RESISTANCE; Science & Technology; CHALLENGE; Virology; T-CELLS; HIV-1-INFECTED CELLS; MONOCLONAL-ANTIBODIES; bNAbs; HIV-1 ENVELOPE GLYCOPROTEIN; ADCC; THERAPY; neutralization; ADCP; TYPE-1; SHIV INFECTION
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term human immunodeficiency virus (HIV) remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth, as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the abilities of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and nonneutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain dependent. Moreover, we observe a strong correlation between the neutralization potencies and nonneutralizing effector functions of bNAbs against the transmitted/ founder SHIV CH505. Finally, we identify several triple bNAb combinations comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.