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Research Efforts Focus on Link Between Hormonal Contraceptives and HIV Infection

Source: Brigham and Women's - On a Mission
Date: 02/20/2019
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According to the World Health Organization, more than half of all married or in-union women of reproductive age use some form of contraception. Additionally, the number of women around the globe who either use contraception or have an unmet need for family planning is expected to grow by more than 900 million over the next decade.

One popular form of birth control is injectable hormonal contraceptives, predominantly the progestin-only form known as depot medroxyprogesterone acetate (DMPA, Depo-Provera®). Yet growing evidence has linked this form of contraception to an increased risk of HIV acquisition and transmission. Researchers at Brigham and Women’s Hospital are focused on determining the underlying causes for this connection and getting the word out about this important public health issue, which affects both women and men.

“This situation is particularly concerning because DMPA is the most commonly used contraceptive method in sub-Saharan Africa, the region that bears an estimated 70 percent of the global HIV infection burden,” said director of the Laboratory of Genital Tract Biology at Brigham and Women’s Hospital and Harvard University. “Our research provides a biologic explanation for the risks and variations in vulnerability to the potential adverse effects of hormonal contraception.”

Work coming out of Dr. Fichorova’s lab also has contributed to the understanding of inflammation and dysbiosis in women and newborns. Other research has looked at how bacteria, protozoan parasites and viruses act in concert to modify human host immunity. In 2018, Dr. Fichorova’s team received an Innovation Award from the Brigham Research Institute to translate their research and recently filed inventions into a novel live biotherapeutic for treatment of vaginal dysbiosis to prevent these conditions.

For the past five years, much of Dr. Fichorova’s research has focused on understanding how and why certain types of hormonal contraceptives change a woman’s biological defenses against infections—and HIV infection in particular. “If we can unveil the molecular pathways that lead to a predisposition to infection, we can discover novel drug targets for preventive medicine,” she said. “At the same time, we hope to lift a significant barrier to the rational design of new, safer contraceptive technologies.”

In one study, Dr. Fichorova and her colleagues analyzed cervical swabs and other data taken from more than 800 women enrolled in family planning clinics in Uganda and Zimbabwe. A major finding was that DMPA was associated with cervical immune imbalance and biomarkers of inflammation that were also associated with higher risk of HIV seroconversion in these women in the next three months.

The team also found higher shedding of HIV in those who seroconverted, thus suggesting pathways for both higher acquisition and transmission of the virus. They showed that DMPA had even broader immune-suppressive effects when acting on the background of abnormal vaginal microbiota characterized by lower abundance of lactobacilli and overgrowth of potentially pathogenic residential bacteria, a condition most often diagnosed as bacterial vaginosis. The data suggested that not only sexually transmitted infections such as herpes but also non-sexually transmitted reproductive tract infections and dysbiosis can make women more vulnerable to the side effects of DMPA.

To a lesser extent, changes in the cervical immune environment were also found in women taking a type of oral contraceptive where another synthetic progestin (levonorgestrel) was combined with synthetic estrogen.

Dr. Fichorova’s lab also has brought to the spotlight the fact that certain species of lactobacilli act as a sentinel of good health in the female reproductive tract, emphasizing the importance of treating conditions that are not sexually transmitted, such as bacterial vaginosis and yeast infections. Non-sexually transmitted vaginal bacteria prevalent in bacterial vaginosis can ascend to the uterus and cause placental epigenetic changes and systemic perinatal inflammation, leading to serious adverse reproductive and child health outcomes.

“Research enabling the design of safer contraceptive technologies is urgently needed. Women of reproductive age should not have to face impossible choices between preventing an unplanned pregnancy and preventing a devastating infection,” Dr. Fichorova concluded. “Understanding, properly diagnosing and treating non-sexually transmitted vaginal dysbiosis should be promoted as a powerful tool for prevention of contraceptives’ side effects as well as adverse pregnancy outcomes.”

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HIV infection prematurely ages humans by an average of 5 years

Source: Cell Press
Date: 04/21/16
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Thanks to combination antiretroviral therapy, many people with HIV can be expected to live decades after being infected. Yet doctors have observed that these patients often show signs of premature aging. Now a study published April 21 in Molecular Cell has applied a highly accurate biomarker to measure just how much HIV infection ages people at the biological level–an average of almost 5 years.

“The medical issues in treating people with HIV have changed,” says Howard Fox, a Professor in the Department of Pharmacology and Experimental Neuroscience at the University of Nebraska Medical Center and one of the authors of the new study. “We’re no longer as worried about infections that come from being immunocompromised. Now we worry about diseases related to aging, like cardiovascular disease, neurocognitive impairment, and liver problems.”

The tool used in the new study looks at epigenetic changes in people’s cells. Epigenetic changes affect the DNA, but not the DNA sequence. Once they occur, they are passed down from one generation of cell to the next, influencing how genes are expressed. The particular epigenetic change used as a biomarker in this research was methylation, the process by which small chemical groups are attached to DNA. Methylation of DNA can impact how genes get translated into proteins.

“What we’ve seen in previous studies is that as we age, methylation across the entire genome changes,” says Trey Ideker, a Professor of Genetics in the Department of Medicine at the University of California San Diego and the study’s other corresponding author. “Some people call it entropy or genetic drift. Although we’re not sure of the exact mechanism by which these epigenetic changes lead to symptoms of aging, it’s a trend that we can measure inside people’s cells.”

The 137 patients included in the analysis were enrolled in CHARTER (the CNS Antiretroviral Therapy Effects Research study), a long-term study aimed at monitoring HIV-infected individuals who are being treated with combination antiretroviral therapy. Subjects who were chosen didn’t have other health conditions that could skew the results. 44 HIV-negative control subjects were also included in the initial analysis. An independent group of 48 subjects, both HIV positive and negative, was used to confirm the findings.

In addition to the discovery that HIV infection led to an average advance in biological aging of 4.9 years, the researchers note that such a change correlates with an increased risk of mortality of 19%.

“We set out to look at the effects of HIV infection on methylation, and I was surprised that we found such a strong aging effect,” Ideker says.

“Another thing that was surprising was that there was no difference between the methylation patterns in those people who were recently infected [less than five years] and those with chronic infection [more than 12 years],” Fox adds.

The investigators say it’s possible drugs could eventually be developed to target the kinds of epigenetic changes observed in the study. But the more immediate implications are much simpler: they note that people infected with HIV should be aware that they’re of greater risk for age-related diseases and work to diminish those risks by making healthy lifestyle choices regarding exercise, diet, and drug, alcohol, and tobacco use.

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Antibody Combination Puts HIV on the Ropes

Source: Rockefeller University, Newswire
Date: 01/25/17
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Without antiretroviral drug treatment, the majority of people infected with HIV ultimately develop AIDS, as the virus changes and evolves beyond the body’s ability to control it. But a small group of infected individuals—called elite controllers—possess immune systems capable of defeating the virus. They accomplish this by manufacturing broadly neutralizing antibodies, which can take down multiple forms of HIV.

Now a study using antibodies from one of these elite controllers has shown that a combination of three such antibodies can completely suppress the virus in HIV-infected mice. The findings, from the laboratory of Michel C. Nussenzweig, who is Zanvil A. Cohn and Ralph M. Steinman Professor at The Rockefeller University and head of the Laboratory of Molecular Immunology, are being reported in Science Translational Medicine.

“Some people with HIV produce these antibodies, but most of the time the virus eventually escapes them through mutations in the antibody’s corresponding epitope,” says postdoctoral fellow Natalia Freund, the study’s first author. The epitope is the part of the virus that antibodies recognize and attach themselves to, and this ability to mutate makes HIV particularly tricky to tame. It ensures that once the virus is in their bodies, people remain infected forever, and this may be the biggest roadblock in developing immune therapies to overcome the virus.

Tug of war

“Think of the relationship between the antibodies and the virus as an arms race that goes on and on,” Freund says. “By mutating, some of the virus may escape the antibodies and continue growing. Years later, the body may produce new broadly neutralizing antibodies against the escaped virus, which in turn may mutate and escape yet again.”

“What we’ve shown in this study is that after several rounds of escape from these particular antibodies, the virus seems to run out of options,” she adds. “In this particular case, HIV eventually loses this arms race.”

An elite controller’s immune system can defeat the virus by coming up with new broadly neutralizing antibodies, and also by producing cytotoxic T cells—immune cells that can recognize and destroy infected cells to immobilize the virus. The patient whose HIV response created antibodies for the study has been working with the Rockefeller team for 10 years, contributing his blood serum for their research. He was infected at least three decades ago, and has developed three different types of broadly neutralizing antibodies that bind to three different sites on the virus.

The remarkable thing about his antibodies is that they seem to complement one another’s activity, completely shutting down HIV.

The investigators gave the three antibodies, called BG18, NC37, and BG1, to HIV-infected mice whose immune systems had been modified to more closely resemble those of humans. They found that the trio rendered the virus undetectable in two-thirds of the mice three weeks after it was administered.

“This study validates the approach of using three different antibodies to control HIV infection,” Freund concludes, “pointing the way toward a potential new treatment for people infected with HIV.”