Tenascin-C is an innate broad-spectrum, HIV-1–neutralizing protein in breast milk
| Autor: | Harold P. Erickson, Erika L. Kunz, Kimberly H. Barbas, Hua-Xin Liao, Tomoo Ohashi, Genevieve G. Fouda, Lisa Stamper, Joshua D. Amos, Frederick H. Jaeger, S. Munir Alam, Brooke E. Liebl, M.A. Moseley, Sallie R. Permar, Kara Anasti, Carrie Ho |
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| Rok vydání: | 2013 |
| Předmět: |
Chemokine
medicine.drug_class Blotting Western Tenascin Breast milk V3 loop Monoclonal antibody Mass Spectrometry Virus Cell Line Inhibitory Concentration 50 Viral Envelope Proteins medicine Humans Immunoprecipitation Receptor Acquired Immunodeficiency Syndrome Multidisciplinary Dose-Response Relationship Drug Milk Human biology Tenascin C virus diseases Biological Sciences Chromatography Ion Exchange Virology Infectious Disease Transmission Vertical Immunology HIV-1 biology.protein Female |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:18220-18225 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1307336110 |
| Popis: | Achieving an AIDS-free generation will require elimination of postnatal transmission of HIV-1 while maintaining the nutritional and immunologic benefits of breastfeeding for infants in developing regions. Maternal/infant antiretroviral prophylaxis can reduce postnatal HIV-1 transmission, yet toxicities and the development of drug-resistant viral strains may limit the effectiveness of this strategy. Interestingly, in the absence of antiretroviral prophylaxis, greater than 90% of infants exposed to HIV-1 via breastfeeding remain uninfected, despite daily mucosal exposure to the virus for up to 2 y. Moreover, milk of uninfected women inherently neutralizes HIV-1 and prevents virus transmission in animal models, yet the factor(s) responsible for this anti-HIV activity is not well-defined. In this report, we identify a primary HIV-1-neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing, yet its antimicrobial properties have not previously been established. Purified TNC captured and neutralized multiclade chronic and transmitted/founder HIV-1 variants, and depletion of TNC abolished the HIV-1-neutralizing activity of milk. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by V3 loop- (19B and F39F) and chemokine coreceptor binding site-directed (17B) monoclonal antibodies. Our results demonstrate the ability of an innate mucosal host protein found in milk to neutralize HIV-1 via binding to the chemokine coreceptor site, potentially explaining why the majority of HIV-1-exposed breastfed infants are protected against mucosal HIV-1 transmission. |
| Databáze: | OpenAIRE |
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