Opportunities to Exploit Non-Neutralizing HIV-Specific Antibody Activity

Abstract

Antibodies act as a nexus between innate and adaptive immunity: they provide a means to engage a spectrum of innate immune effector cells in order to clear viral particles and infected cells, and prime antigen presentation. This functional landscape is remarkably complex, and depends on antibody isotype, subclass, and glycosylation; the expression levels and patterns of a suite of Fc receptors with both complementary and opposing activities; and a host of innate immune cells capable of differential responses to opsonized particles and present at different sites. In vivo, even neutralizing antibodies rely on their ability to act as molecular beacons and recruit innate immune effector cells in order to provide protection, and results from both human and macaque studies have implicated these effector functions in vaccine-mediated protection. Thus, while enhancing effector function is a tractable handle for potentiating antibody-mediated protection from HIV infection, success will depend critically on leveraging understanding of the means by which antibodies with specific functional profiles could be elicited, which effector functions could provide optimal protection, and perhaps most critically, how to efficiently recruit the innate effector cells present at sites of infection.

Highly parallel characterization of IgG Fc binding interactions

“…[12][13][14][15] Collectively, these natural mechanisms offer a path for similar rational induction of antibody responses with specific functional profiles via vaccination. 16 Furthermore, beyond relatively well-characterized FcγR and complement proteins, a growing number of diverse and structurally unrelated Fc-binding proteins have been identified, ranging from the pH-sensitive neonatal Fc receptor 17 to C-type lectins such as dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), 18 FcR-Like receptors, 19,20 mannose-binding lectin 2 (MBL2), 21 TRIM21, 22 macrophage mannose receptor (MMR), 23 and Dectin-1. 24 Probing the recognition properties of these and other FcR for engineered and and Margaret e ackerman naturally-produced IgG represents an important avenue to enhance our understanding of their potential role in antibody activity in vivo.…”

Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys

“…In addition to neutralization, antibodies mediate a wide variety of additional antiviral functions through their ability to interact with Fc receptors, complement, and lectin-like proteins (12, 13). Previous studies showed that antibody-dependent cellular phagocytosis (ADCP) (14) and antibody-dependent complement deposition (ADCD) responses correlated with protective efficacy in rhesus monkeys (6).…”

Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs

“…In addition to direct neutralization of virus, antibodies can facilitate the recognition and elimination of infected cells through Fc-mediated mechanisms such as antibodydependent cell-mediated cytotoxicity and complement-mediated lysis (12)(13)(14). In rhesus macaque and humanized mouse animal models of simian-human immunodeficiency virus (SHIV) and HIV-1 infection, respectively, HIV-1 MAbs have been shown to be effective as both immunoprophylactic and immunotherapeutic agents (15)(16)(17)(18)(19)(20).…”