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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Amino Acids
  • Epitope Mapping
  • Epitopes / chemistry
  • Epitopes / immunology
  • Glycosylation
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / immunology
  • HIV-1 / metabolism*
  • Humans
  • Models, Molecular
  • Neutralization Tests
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Recombinant Proteins
  • Tenascin / chemistry*
  • Tenascin / metabolism*
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism*


  • Amino Acids
  • Epitopes
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (305-321)
  • Peptide Fragments
  • Recombinant Proteins
  • Tenascin
  • env Gene Products, Human Immunodeficiency Virus