Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk.
Abstract
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.
Type
Journal articleSubject
Cell LineMilk, Human
Humans
HIV-1
Acquired Immunodeficiency Syndrome
Tenascin
Viral Envelope Proteins
Blotting, Western
Chromatography, Ion Exchange
Immunoprecipitation
Inhibitory Concentration 50
Dose-Response Relationship, Drug
Female
Mass Spectrometry
Infectious Disease Transmission, Vertical
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https://hdl.handle.net/10161/16467Published Version (Please cite this version)
10.1073/pnas.1307336110Publication Info
Fouda, Genevieve G; Jaeger, Frederick H; Amos, Joshua D; Ho, Carrie; Kunz, Erika L;
Anasti, Kara; ... Permar, Sallie R (2013). Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk.
Proceedings of the National Academy of Sciences of the United States of America, 110(45). 10.1073/pnas.1307336110. Retrieved from https://hdl.handle.net/10161/16467.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
S. Munir Alam
Professor in Medicine
Research Interests.
The Alam laboratory’s primary research is focused on understanding the biophysical
properties of antigen-antibody binding and the molecular events of early B cell activation
using the HIV-1 broadly neutralizing antibody (bnAb) lineage models. We are studying
how HIV-1 Envelope proteins of varying affinities are sensed by B cells expressing
HIV-1 bnAbs or their germline antigen receptors and initiate early signaling events
for their activation. In the lon
Harold Paul Erickson
James B. Duke Distinguished Professor of Cell Biology
Cytoskeleton: It is now clear that the actin and microtubule cytoskeleton originated
in bacteria. Our major research is on FtsZ, the bacterial tubulin homolog, which assembles
into a contractile ring that divides the bacterium. We have studied FtsZ assembly
in vitro, and found that it assembles into thin protofilaments (pfs). Dozens of these
pfs are further clustered to form the contractile Z-ring in vivo. Some important discoveries
in the last ten years include:
&bul
Genevieve Giny Fouda
Associate Professor in Pediatrics
Dr Fouda's research interest is in understanding infant immune responses in the setting
of infection and vaccination. Her current work focuses on HIV mother to child transmission.
Hua-Xin Liao
Adjunct Professor in the Department of Medicine
Dr. Liao is a Professor of Medicine and Research Director of Duke Human Vaccine Institute.
Dr. Liao is a MD virologistt rained in China. In early 1980’s, Dr. Liao made
major contributions to the first isolation of epidemic hemorrhagic fever virus (hataanvirus)
from Apodemus agraius using tissue culture in China. The successful identification
and isolation of Hataanvirus enabled the early diagnosis and treatment of the disease,
and advancement of HFRS research towards prevention by de
Martin Arthur Moseley III
Adjunct Professor in the Department of Cell Biology
Tomoo Ohashi
Assistant Research Professor of Cell Biology
Sallie Robey Permar
Wilburt C. Davison Distinguished Professor
Dr. Permar's work focuses on the development of vaccines to prevent vertical transmission
of neonatal viral pathogens. She has utilized the nonhuman primate model of HIV/AIDS
to characterize the virus-specific immune responses and virus evolution in breast
milk and develop a maternal vaccine regimen for protection against breast milk transmission
of HIV. In addition, Dr. Permar's lab has advanced the understanding of HIV-specific
immune responses and virus evolution in vertically-transmitting an
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