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Mucosal Immunol. 2019 Jul;12(4):1004-1012. doi: 10.1038/s41385-019-0164-2. Epub 2019 Apr 11.

Determinants of Tenascin-C and HIV-1 envelope binding and neutralization.

Author information

1
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
2
Department of Cell Biology, Duke University, Durham, NC, USA.
3
Department of Chemistry, University of Kansas, Lawrence, Kansas, USA.
4
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. sallie.permar@duke.edu.
5
Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. sallie.permar@duke.edu.
6
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. sallie.permar@duke.edu.

Abstract

Interactions between innate antiviral factors at mucosal surfaces and HIV-1 virions contribute to the natural inefficiency of HIV-1 transmission and are a platform to inform the development of vaccine and nonvaccine strategies to block mucosal HIV-1 transmission. Tenascin-C (TNC) is a large, hexameric extracellular matrix glycoprotein identified in breast milk and genital fluids that broadly neutralizes HIV-1 via interaction with the HIV-1 Envelope (Env) variable 3 (V3) loop. In this report, we characterize the specific determinants of the interaction between TNC and the HIV-1 Env. We observed that TNC binding and neutralization of HIV-1 is dependent on the TNC fibrinogen-like globe (fbg) and fibronectin-type III (fn) domains, oligomerization, and its newly-mapped glycan structure. Moreover, we observed that TNC-mediated neutralization is also dependent on Env V3 residues 321/322 and 326/327, which surround the IGDIR motif of the V3 loop, as well the N332 glycan, which is critical to the broadly neutralizing activity of glycan-dependent V3-specific antibodies such as PGT128. Our results demonstrate a striking parallel between innate and adaptive immune mechanisms of broad HIV neutralization and provide further insight into the host protein-virus interactions responsible for the natural inefficiency of mucosal HIV-1 transmission.

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