The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids

Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected ind...

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Published in:	PloS one Vol. 11; no. 5; p. e0155261
Main Authors:	Mansour, Robin G, Stamper, Lisa, Jaeger, Frederick, McGuire, Erin, Fouda, Genevieve, Amos, Joshua, Barbas, Kimberly, Ohashi, Tomoo, Alam, S Munir, Erickson, Harold, Permar, Sallie R
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 16-05-2016 Public Library of Science (PLoS)
Subjects:	Antibodies, Neutralizing - immunology Antigens Antiviral agents Binding sites Biology and Life Sciences Breast Breast milk Breastfeeding & lactation Cancer Care and treatment Cervix Uteri - immunology Colostrum Disease transmission Extracellular Fluid - immunology Extracellular matrix Female Fluids Genitalia Health aspects HIV HIV Antibodies - immunology HIV Envelope Protein gp120 - immunology HIV Envelope Protein gp120 - metabolism HIV infections HIV Infections - immunology HIV Infections - virology HIV-1 - drug effects HIV-1 - immunology Human immunodeficiency virus Human immunodeficiency virus 1 Humans Hydrogen-Ion Concentration Immunity, Innate Immunoglobulin G Immunoglobulin G - immunology Immunoglobulins Infections Male Medicine and Health Sciences Milk Milk Proteins - immunology Milk Proteins - pharmacology Milk, Human - immunology Monoclonal antibodies Mucosa Mucous Membrane - immunology Mucous Membrane - metabolism Neutralization Tests Neutralizing Peptide Fragments - immunology Peptide Fragments - metabolism pH effects Prevention Proteases Protein Binding Proteins Recombinant Proteins Research and Analysis Methods Review boards Semen Semen - immunology Systematic review Tenascin Tenascin - immunology Tenascin - pharmacology Tenascin C Vagina United States North Carolina United States > US
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Summary:	Tenascin-C (TNC) is a newly identified innate HIV-1-neutralizing protein present in breast milk, yet its presence and potential HIV-inhibitory function in other mucosal fluids is unknown. In this study, we identified TNC as a component of semen and cervical fluid of HIV-1-infected and uninfected individuals, although it is present at a significantly lower concentration and frequency compared to that of colostrum and mature breast milk, potentially due to genital fluid protease degradation. However, TNC was able to neutralize HIV-1 after exposure to low pH, suggesting that TNC could be active at low pH in the vaginal compartment. As mucosal fluids are complex and contain a number of proteins known to interact with the HIV-1 envelope, we further studied the relationship between the concentration of TNC and neutralizing activity in breast milk. The amount of TNC correlated only weakly with the overall innate HIV-1-neutralizing activity of breast milk of uninfected women and negatively correlated with neutralizing activity in milk of HIV-1 infected women, indicating that the amount of TNC in mucosal fluids is not adequate to impede HIV-1 transmission. Moreover, the presence of polyclonal IgG from milk of HIV-1 infected women, but not other HIV-1 envelope-binding milk proteins or monoclonal antibodies, blocked the neutralizing activity of TNC. Finally, as exogenous administration of TNC would be necessary for it to mediate measurable HIV-1 neutralizing activity in mucosal compartments, we established that recombinantly produced TNC has neutralizing activity against transmitted/founder HIV-1 strains that mimic that of purified TNC. Thus, we conclude that endogenous TNC concentration in mucosal fluids is likely inadequate to block HIV-1 transmission to uninfected individuals.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: RGM LS FJ EM GF SMA SRP. Performed the experiments: RGM LS FJ EM JA. Analyzed the data: RGM LS FJ EM GF SMA SRP. Contributed reagents/materials/analysis tools: FJ KB TO SMA HE. Wrote the paper: RGM LS SMA HE SRP. Competing Interests: The authors have declared that no competing interests exist. Current address: Duke University Medical Center, Human Vaccine Institute, Box 103020, Durham, NC, 27710, United States of America
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0155261