Protective mechanisms of nonneutralizing antiviral antibodies

Abstract

Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.

Fig 1. nNAb-mediated antiviral effector functions following antigen binding to Fab.

NK cells can exhibit ADCC by detecting target cells (i.e., virus-infected cells) opsonized by antibodies via the FcγRIII (CD16) receptor and induce apoptosis by releasing cytotoxic granules. Macrophages and other phagocytes perform ADCP by recognizing opsonized viral particles via the FcγRI (CD64) and FcγRIIA (CD32) receptors leading to virolysis and downstream antigen presentation of viral antigen. Antibodies activate the classical complement pathway after binding to the soluble complement complex, C1q. In addition to viral aggregation and opsonization, antibody-dependent complement fixation on viral or target cell membranes can lead to the formation of the pore-forming MAC and ADCML. Cooperation between nNAb (green) binding that exposes epitopes for neutralizing antibody (yellow) binding can enhance the efficacy of virus neutralization. Antibodies can block viral replication intracellularly; for dsRNA viruses that maintain an intact innermost capsid inside cells, antibodies can block mRNA egress. Intracellular antibodies can also be bound by TRIM21, which leads to proteasomal degradation of the virus–antibody complex and can result in enhanced MHC class I antigen presentation. Created with Biorender.com. ADCC, antibody-dependent cellular cytotoxicity; ADCML, antibody-dependent complement-mediated lysis; ADCP, antibody-dependent cellular phagocytosis; MAC, membrane attack complex; NK, natural killer; nNAb, nonneutralizing antibody.