Breast Milk Protein May Be Key to Protecting Babies From HIV Infection

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Released: 10/16/2013 3:15 PM EDT
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Source Newsroom: Duke Medicine

Newswise — DURHAM, N.C. – A substance in breast milk that neutralizes HIV and may protect babies from acquiring HIV from their infected mothers has been identified for the first time by researchers at Duke Medicine.

The protein, called Tenascin-C or TNC, had previously been recognized as playing a role in wound healing, but had not been known to have antimicrobial properties. The discovery could lead to potential new HIV-prevention strategies.

Reporting in the journal Proceedings of the National Academy of Sciences during the week of Oct. 21, 2013, the researchers describe how the TNC protein in breast milk binds to and neutralizes the HIV virus, potentially protecting exposed infants who might otherwise become infected from repeated exposures to the virus.

“Even though we have antiretroviral drugs that can work to prevent mother-to-child transmission, not every pregnant woman is being tested for HIV, and less than 60 percent are receiving the prevention drugs, particularly in countries with few resources,” said senior author Sallie Permar, M.D., Ph.D., assistant professor of pediatrics, immunology and molecular genetics and microbiology at Duke. “So there is still a need for alternative strategies to prevent mother-to-child transmission, which is why this work is important.”

Worldwide in 2011, an estimated 330,000 children acquired HIV from their mothers during pregnancy or birth, or through breastfeeding according to UNICEF. As international health organizations have set a goal of eliminating mother-to-child infections, researchers have worked to develop safe and affordable alternatives to antiretroviral therapy that can be used to block HIV transmission to infants.

Permar and colleagues focused on breast milk, which has long been recognized as having some protective quality that inhibits mother-to-child transmission despite multiple daily exposures over months and even years of nursing. Earlier studies had identified some antiviral properties in breast milk, but the majority of the HIV-neutralizing activity of breast milk remained unexplained. More recent studies pointed to a large protein that had yet to be identified.

In their study, the Duke team screened mature milk samples from uninfected women for neutralizing activity against a panel of HIV strains, confirming that all of the detectable HIV-neutralization activity was contained in the high molecular weight portion. Using a multi-step protein separation process, the researchers narrowed the detectable HIV-neutralization activity to a single protein, and identified it as TNC.

“TNC is a component of the extracellular matrix that is integral to how tissues hold themselves together,” Permar said, noting that co-author Harold Erickson, Ph.D., professor of cell biology at Duke, was among the first to identify and describe TNC in the 1980s. “This is a protein involved during wound healing, playing a role in tissue repair. It is also known to be important in fetal development, but its reason for being a component of breast milk or its antiviral properties had never been described.”

Further analysis described how TNC works against HIV by blocking virus entry. The protein is uniquely effective in capturing virus particles and neutralizes the virus, specifically binding to the HIV envelope. These properties provide widespread protection against infection.

“It’s likely that TNC is acting in concert with other anti-HIV factors in breast milk, and further research should explore this,” Permar said. “But given TNC’s broad-spectrum HIV-1-binding and neutralizing activity, it could be developed as an HIV-prevention therapy, given orally to infants prior to breastfeeding, similar to the way oral rehydration salts are routinely administered to infants in developing regions.”

Permar said TNC would also appear to be inherently safe, since it is a naturally occurring component of breast milk, and it may avoid the problem of HIV resistance to antiretroviral regimens that complicate maternal/infant applications.

“The discovery of the HIV inhibiting effect of this common protein in breast milk provides a potential explanation for why nursing infants born to HIV-infected mothers do not become infected more often than they do,” said Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute. “It also provides support for inducing inhibitory factors in breast milk that might be even more protective, such as antibodies, that would completely protect babies from HIV infection in this setting.”

In addition to Permar, co-senior author was S. Munir Alam. Other authors include Genevieve G. Fouda, Frederick H. Jaeger, Joshua D. Amos, Carrie Ho, Erika L. Kunz, Kara Anasti, Lisa W. Stamper, Brooke E. Liebl; Kimberly H. Barbas, Tomoo Ohashi, M. Arthur Moseley, Hua-Xin Liao and Harold P. Erickson.

The study was funded by the Doris Duke Charitable Foundation Clinical Scientist Development Award; Duke University School of Medicine; Center for HIV/AIDS Vaccine Immunology; and the National Institute of Allergic and Immunologic Diseases (U19 AI067854) (K08AI087992) (CA047056).

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Scientists Identify Protein Linking Exercise to Brain Health

Newswise — BOSTON — A protein that is increased by endurance exercise has been isolated and given to non-exercising mice, in which it turned on genes that promote brain health and encourage the growth of new nerves involved in learning and memory, report scientists from Dana-Farber Cancer Institute and Harvard Medical School.

The findings, reported in the journal Cell Metabolism, help explain the well-known capacity of endurance exercise to improve cognitive function, particularly in older people. If the protein can be made in a stable form and developed into a drug, it might lead to improved therapies for cognitive decline in older people and slow the toll of neurodegenerative diseases such Alzheimer’s and Parkinson’s, according to the investigators.

“What is exciting is that a natural substance can be given in the bloodstream that can mimic some of the effects of endurance exercise on the brain,” said Bruce Spiegelman, PhD, of Dana-Farber and HMS. He is co-senior author of the publication with Michael E. Greenberg, PhD, chair of neurobiology at HMS.

The Spiegelman group previously reported that the protein, called FNDC5, is produced by muscular exertion and is released into the bloodstream as a variant called irisin. In the new research, endurance exercise – mice voluntarily running on a wheel for 30 days – increased the activity of a metabolic regulatory molecule, PGC-1a, in muscles, which spurred a rise in FNDC5 protein. The increase of FNDC5 in turn boosted the expression of a brain-health protein, BDNF (brain-derived neurotrophic protein) in the dentate gyrus of the hippocampus, a part of the brain involved in learning and memory.

It has been found that exercise stimulates BDNF in the hippocampus, one of only two areas of the adult brain that can generate new nerve cells. BDNF promotes development of new nerves and synapses – connections between nerves that allow learning and memory to be stored – and helps preserve the survival of brain cells.

How exercise raises BDNF activity in the brain wasn’t known; the new findings linking exercise, PGC-1a, FNDC5 and BDNF provide a molecular pathway for the effect, although Spiegelman and his colleagues suggest there are probably others.

Having shown that FNDC5 is a molecular link between exercise and increased BDNF in the brain, the scientists asked whether artificially increasing FNDC5 in the absence of exercise would have the same effect. They used a harmless virus to deliver the protein to mice through the bloodstream, in hopes the FNDC5 could reach the brain and raise BDNF activity. Seven days later, they examined the mouse brains and observed a significant increase in BDNF in the hippocampus.

“Perhaps the most exciting result overall is that peripheral deliver of FNDC5 with adenoviral vectors is sufficient to induce central expression of Bdnf and other genes with potential neuroprotective functions or those involved in learning and memory,” the authors said. Spiegelman cautioned that further research is needed to determine whether giving FNDC5 actually improves cognitive function in the animals. The scientists also aren’t sure whether the protein that got into the brain is FNDC5 itself, or irisin, or perhaps another variant of the protein.

Spiegelman said that development of irisin as a drug will require creating a more stable form of the protein.

The first author of the report is Christiane Wrann, PhD, in the Spiegelman lab.
The research was supported by the JPB Foundation and National Institutes of Health (DK31405 and DK90861).

About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center, designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Boston Children’s Hospital as Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Facebook and on Twitter.