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Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):14862-14867. doi: 10.1073/pnas.1820165116. Epub 2019 Jul 3.

Antigen structure affects cellular routing through DC-SIGN.

Author information

1
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
2
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.
3
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706.
4
Department of Molecular Virology and Oncology, University of Wisconsin-Madison, Madison, WI 53706.
5
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; kiesslin@mit.edu.

Abstract

Dendritic cell (DC) lectins mediate the recognition, uptake, and processing of antigens, but they can also be coopted by pathogens for infection. These distinct activities depend upon the routing of antigens within the cell. Antigens directed to endosomal compartments are degraded, and the peptides are presented on major histocompatibility complex class II molecules, thereby promoting immunity. Alternatively, HIV-1 can avoid degradation, as virus engagement with C-type lectin receptors (CLRs), such as DC-SIGN (DC-specific ICAM-3-grabbing nonintegrin) results in trafficking to surface-accessible invaginated pockets. This process appears to enable infection of T cells in trans We sought to explore whether antigen fate upon CLR-mediated internalization was affected by antigen physical properties. To this end, we employed the ring-opening metathesis polymerization to generate glycopolymers that each display multiple copies of mannoside ligand for DC-SIGN, yet differ in length and size. The rate and extent of glycopolymer internalization depended upon polymer structure-longer polymers were internalized more rapidly and more efficiently than were shorter polymers. The trafficking, however, did not differ, and both short and longer polymers colocalized with transferrin-labeled early endosomes. To explore how DC-SIGN directs larger particles, such as pathogens, we induced aggregation of the polymers to access particulate antigens. Strikingly, these particulate antigens were diverted to the invaginated pockets that harbor HIV-1. Thus, antigen structure has a dramatic effect on DC-SIGN-mediated uptake and trafficking. These findings have consequences for the design of synthetic vaccines. Additionally, the results suggest strategies for targeting DC reservoirs that harbor viral pathogens.

KEYWORDS:

C-type lectin; HIV; antigen; endocytosis; polymer

PMID:
31270240
PMCID:
PMC6660738
[Available on 2020-01-03]
DOI:
10.1073/pnas.1820165116

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