Non-neutralizing Antibodies May Contribute to Suppression of SIVmac239 Viremia in Indian Rhesus Macaques

Nuria Pedreño-Lopez,Brandon C Rosen,Walter J Flores,Mauricio A Martins,Galit Alter,Diogo M Magnani,David I Watkins,Thomas B Voigt,Christopher L Parks,Jeffrey D Lifson,Michael J Ricciardi,Eva G Rakasz,Kim L Weisgrau,Kristin Crosno,Matthew J Gorman

doi:10.3389/fimmu.2021.657424

Abstract

The antiviral properties of broadly neutralizing antibodies against HIV are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. While current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (SIV) and HIV, the ability of these responses to restrict lentivirus transmission and replication remains controversial. Here, we investigated the antiviral properties of non-neutralizing antibodies in a group of Indian rhesus macaques (RMs) that were vaccinated with vif, rev, tat, nef, and env, as part of a previous study conducted by our group. These animals manifested rapid and durable control of viral replication to below detection limits shortly after SIVmac239 infection. Although these animals had no serological neutralizing activity against SIVmac239 prior to infection, their pre-challenge titers of Env-binding antibodies correlated with control of viral replication. To assess the contribution of anti-Env humoral immune responses to virologic control in two of these animals, we transiently depleted their circulating antibodies via extracorporeal plasma immunoadsorption and inhibition of IgG recycling through antibody-mediated blockade of the neonatal Fc receptor. These procedures reduced Ig serum concentrations by up to 80% and temporarily induced SIVmac239 replication in these animals. Next, we transferred purified total Ig from the rapid controllers into six vaccinated RMs one day before intrarectal challenge with SIVmac239. Although recipients of the hyperimmune anti-SIV Ig fraction were not protected from infection, their peak and chronic phase viral loads were significantly lower than those in concurrent unvaccinated control animals. Together, our results suggest that non-neutralizing Abs may play a role in the suppression of SIVmac239 viremia.

Highlights

Antibodies (Abs) are one of the two major components of the adaptive immune response and are key in vaccine development
To identify a shared Ab signature among the five vaccinated rapid controllers from our previous vaccine trial, we assessed the vaccine-induced Ab responses developed in each animal at the time of the first challenge by systems serology [12]
Since Barouch et al reported that protected Ad26vaccinated rhesus macaques (RMs) had developed highly polyfunctional Abs [3], we evaluated the capacity of our vaccine-induced Abs to mediate Ab-dependent cellular phagocytosis (ADCP), Abdependent complement deposition (ADCD) and NK cell activation (Figure 1B)

Summary

Introduction

Antibodies (Abs) are one of the two major components of the adaptive immune response and are key in vaccine development. Protective Abs mediate pathogen control and clearance by neutralization and Fc effector functions. While neutralizing Abs can prevent infection and suppress HIV/SIV replication in humans and Indian rhesus macaques (RMs), high levels of neutralizing Ab titers against a neutralization resistant tier 3 virus not yet been induced by vaccination. The results of adenovirus 26 (Ad26) vaccination and transfer studies in RMs [3,4,5] suggested the potential benefit that non-neutralizing Env-binding Abs might have against HIV/SIV. Protection in Ad26-vaccinated RMs was associated with the induction of polyfunctional Abs with the capacity to mediate Fc effector functions, including Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and Abdependent complement deposition (ADCD) [3, 4]

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