Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16

Abstract

Transmission of HIV across mucosal barriers accounts for the majority of HIV infections worldwide. Thus, efforts aimed at enhancing protective immunity at these sites are a top priority, including increasing virus-specific antibodies (Abs) and antiviral activity at mucosal sites. Mucin proteins, including the largest cell-associated mucin, MUC16, help form mucus to provide a physical barrier to incoming pathogens. Here we describe a natural interaction between Abs and MUC16 that is enhanced in specific disease settings such as chronic HIV infection. Binding to MUC16 was independent of IgG subclass, but strongly associated with shorter Ab glycan profiles, with agalactosylated (G0) Abs demonstrating the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16-knockdown, and the MUC16 N-linked glycans were critical for binding. Further, agalactosylated VRC01 captured HIV more efficiently in MUC16. These data point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc-glycosylation, potentially blocking viral movement and sequestering the virus far from the epithelial border. Thus, next-generation vaccines or monoclonal therapeutics may enhance protective immunity by tuning Ab glycosylation to promote the enrichment of Abs at mucosal barriers.

A Functional Role for Antibodies in Tuberculosis

“…Thus, Ab glycosylation differences may reflect differential B cell priming (Mahan et al, 2016; Selman et al, 2012) aimed at directing optimized pathogen- or antigen-specific clearance activity. In autoimmune disease, Ab glycosylation is heavily influenced by inflammation (Bohm et al, 2014), and interestingly, the glycan modifications that are enriched among individuals with Atb are quite similar to those observed in rheumatoid arthritis and HIV infection (Ackerman et al, 2013; Gunn et al, 2016; Parekh et al, 1989) suggesting that high levels of agalactosylated (G0) Abs may emerge in the setting of chronic inflammatory diseases. This may be linked to the non-specific activation of B cells or the induction of unique B cell responses in the setting of persistently high antigen loads.…”

Progress in HIV vaccine development

“…Positive V1V2-specific complement activating Ab was also correlated with lower infection risk in RV144 vaccine recipients. 59 Therefore, though only weakly neutralizing, Ab induced by RV144 may potentially mediate protection through aggregating or immobilizing virions in mucin layers, impeding transverse through mucosal barriers, [60][61][62] via IgG Fcg receptor (FcgR) dependent ADCVI including ADCC, [55][56][57] ADCP, 56,57 Ab-mediated release of cytokines or chemokines and complement-mediated killing. [50][51][52]59,63,64 ( Fig.…”

Systemic and topical use of monoclonal antibodies to prevent the sexual transmission of HIV

“…Nonfucosylated glycan forms on antibodies from elite controllers were shown to minimize viral load during chronic HIV-1 infection through ADCVI [84], and nonfucosylated HIV bNAbs have been made that demonstrate higher affinity for Fcγ RIIIa receptors and enhanced ADCC activity [33]. Furthermore, Fc glycosylation also affects antibody interactions with mucins; antibodies with shorter glycan profiles preferentially associated with MUC16 and captured more virions [85]. These data suggest that modification of Fc glycosylation could improve antibody function in the mucosal environment.…”