Up to 30 percent of HIV patients who are appropriately treated with antiretroviral therapies develop the chronic lung disease emphysema in their lifetime. Now, new research from Weill Cornell Medicine investigators has uncovered a mechanism that might explain why this lung damage occurs.

In the study, published May 9 in Cell Reports, investigators show how the human immunodeficiency virus, or HIV, binds to stem cells, called basal cells, which transform into other types of cells that line the airways. This process reprograms the basal cells, causing them to release enzymes, known as proteases, which can destroy lung tissue and poke holes in walls of the air sacs, where oxygen is exchanged.

“This research is important because although antiretroviral agents have turned HIV into a chronic, rather than deadly, disease, the viral reservoirs that remain in the lungs and other tissue continue to cause serious side effects,” said senior author Dr. Ronald Crystal, chairman of the Department of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine, and a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center. “Now that we have more information about how the HIV virus might cause emphysema, we can learn more about this potential enzyme target and work towards developing a therapy to prevent this lung damage from happening.”

Since antiretroviral agents have been used to treat the 18.2 million people in the world who are HIV positive and have access to these drugs—1.2 million of them in the United States—lifespans have greatly extended. But as HIV positive people have lived longer, they’ve also been diagnosed with degenerative disorders of the brain, heart and lungs at a higher rate than the general population. Many scientists have investigated how long-term HIV treatment leads to these outcomes. Some posit that the antiretroviral drugs themselves might contribute to these issues, while others have investigated the role of inflammatory cells. This study doesn’t discount earlier theories, Dr. Crystal said, but rather reveals a new mechanism by which the virus attaches itself to and reprograms basal airway cells, that should be further investigated as a possible therapeutic target.

To conduct this research, investigators took normal human airway basal cells, collected from the lungs of healthy nonsmokers, and under observation, exposed them to HIV for a set period of time. Rather than entering and reproducing in the basal cells, the virus instead bonded to the basal cells’ surface and reprogrammed them to start producing an enzyme, or protease, which can break down proteins and destroy tissues, called metalloprotease-9. Because investigators know that emphysema, a disease of the air sacs, starts in the airways, this finding suggests that when basal cells take on what Dr. Crystal called a “destructive phenotype,” they start eating away at healthy tissue, which in time, results in emphysema.

“To see how a virus modifies the function of a cell is an important observation,” Dr. Crystal said, noting that the Zika virus operates in a similar manner by infecting neural stem cells and changing their function, which leads to a birth defect characterized by a smaller than normal head and abnormal brain, called microcephaly.

“Our next step is to conduct additional research to determine what the preventative therapeutic target might be,” Dr. Crystal said, adding that the protease is a likely suspect, “and then, since basal cells are so important to normal lung anatomy and lung function, determine the other side effects of this re-programming.”

The study, published March 15 in Immunity, focused on "good" or "commensal" bacteria that live in the human intestine and are essential for digestion and proper immune function. The majority of these commensal bacteria are found in the tube-like inner core of the intestine, called the lumen. The intestine itself acts as a barrier, keeping the bacteria inside the lumen and ensuring that they do not enter the rest of the body. Many reports have demonstrated that if commensal bacteria managed to escape the lumen, they would activate the immune system and cause disease.

But in their study, Weill Cornell Medicine investigators identified a group of commensal bacteria residing in close contact with immune cells outside of the intestinal lumen that defy this thinking. The discovery may alter the way scientists understand diseases like HIV, inflammatory bowel disease, some cancers, and cardiovascular disease.

"For a long time, the assumption was that the human body is essentially sterile and that a physical separation between the immune system and our commensal bacteria was necessary to prevent chronic inflammation," said lead author Dr. Gregory Sonnenberg, an assistant professor of microbiology and immunology in medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. "While this is certainly true for most types of commensal bacteria, our new data demonstrate a special class of commensal bacteria that can closely associate with immune cells in a way that is mutually beneficial for both mammals and the microbes."

To learn more about this population of microbes, the researchers studied "germ-free" mice — rodents that are bred to have no bacteria in their bodies and have no contact with outside bacteria. They added this newly identified class of bacteria, called lymphoid tissue-resident commensal bacteria (LRC), to the mice.

The LRC colonized lymphoid tissues — specifically cells in the immune system — located outside of the intestinal lumen. When Dr. Sonnenberg and his colleagues investigated what the bacteria were doing, they found that they did not cause inflammation as expected. Rather, they did exactly the opposite — they limited the inflammatory response in the immune tissue.

The researchers then tried to experimentally induce intestinal tissue damage and inflammation in the rodents. They found that the mice that had LRC in their lymphoid tissue were protected.

"So it seems that these bacteria residing in lymphoid tissue are actually protecting the mice, rather than driving disease as would be expected," said lead author Thomas Fung, a graduate student in Dr. Sonnenberg's lab. "We further found that the immune responses induced by these bacteria are mutually beneficial; they not only protected mice from experimental tissue damage, but they also facilitated bacteria colonization of lymphoid tissues."

These are early findings, but the implications for human health are important to consider, Dr. Sonnenberg added. For example, the prevailing view is that in people with inflammatory bowel disease, colorectal cancer or HIV infection, commensal bacteria disseminate from the lumen of the intestine into the periphery of the body and promote inflammation.

"Our new data indicate that some unique bacteria residing in lymphoid tissues could instead promote tissue protection and limit inflammation," he said, "and our research highlights that it will be important to consider changes in lymphoid tissue-resident microbes during human health and disease."

The Sonnenberg Laboratory is also investigating whether LRCs can be developed as an innovative therapeutic approach to limit chronic inflammation and promote tissue repair in diseases such as inflammatory bowel disease.

By studying the use of electronic health records, Weill Cornell Medicine investigators aim to transform how patients receive medical care

By Anne Machalinski
Photography by John Abbott

When Dennis Gawrys saw a doctor for the first time in 30 years, he received some shocking news: Not only was the former Marine pre-diabetic, but he had high blood pressure and high cholesterol. He was prescribed a statin to lower his cholesterol and another medication to control his blood pressure, but a year later was diagnosed with type-2 diabetes and hypothyroidism. His doctors added the diabetes drug metformin and a thyroid medication to his daily regimen. "I was so scared," says Gawrys, now 73, of Manhattan. But "knowing that 99 percent of your health is up to you," he took control.

He joined a Weill Cornell Medicine diabetes support group, which he still attends every Tuesday, and started exercising and adhering to a low-carb diet. While those changes offered significant improvements, it wasn't until a decade later — when he logged into an online patient portal called Weill Cornell CONNECT — that he truly felt ownership of his health. Gawrys was able to track his blood test results, cholesterol levels, and hemoglobin A1C score, which measures how well blood sugar is controlled. He could also access and download his medical records before an appointment with a specialist, manage his prescriptions and order refills and send questions to his clinicians. Three years ago, Gawrys reaped the benefits: His doctor took him off metformin, decreased other medications, and downgraded him to a twice-yearly appointment. "The online portal represents a guidepost for me," he says. "While I still have to be vigilant, knowing that the numbers will be there keeps me honest and on top of things."

Gawrys is just one patient, but improving the implementation and use of electronic records and patient portals could ultimately lead to better health outcomes for entire populations. Weill Cornell Medicine scientists are piecing together a nuanced picture of the strengths and weaknesses of these systems — among the most widely recognized aspects of modern healthcare — as part of a broad inquiry by faculty into how to make medical care more accessible, effective and affordable for patients and the people and institutions that provide it. "Problems with quality and cost in the U.S. healthcare system are well recognized," says Dr. Rainu Kaushal, chair of the Department of Healthcare Policy and Research and the Nanette Laitman Distinguished Professor of Healthcare Policy and Research. "We're doing this comprehensive and multidisciplinary research so that each patient gets the right treatment at the right time, every time." In addition to scrutinizing the presentation and use of electronic health records, Weill Cornell Medicine is trying to capitalize on the growing availability of electronic data from millions of patients to make research more patient-centered, powerful and meaningful. Investigators are analyzing data to inform individual patient decisions, such as the cost-effectiveness of treatment regimens for complex conditions, and national policy, such as the efficacy of new healthcare delivery models, like Accountable Care Organizations.

In Gawrys's case, just having easy access to his medical information made a huge difference. But while such portals are used by hundreds of thousands of people, many patients aren't as proactive as he is. About a quarter of the public say they use an online portal — but that leaves out most patients, including many who are dealing with complex conditions and multiple providers, says Dr. Jessica Ancker, an associate professor of healthcare policy and research. Dr. Ancker studies who's using — and not using — these portals, and whether the information that's there is actually helping patients better understand their health and make more informed decisions about their care. Among those most at risk of being left out of the online portal trend are patients who are black, uninsured, elderly, less computer literate, or poor. "This raises some concerns from a public health standpoint," Dr. Ancker says. "It means that we have more work to do to improve these systems so that they're more user-friendly and accessible, even for people who don't have computers."

While the vast majority of doctors and hospitals are now using electronic systems for storing patient data, most are not able to easily share information between institutions, Dr. Ancker says. As a result, patients are left to manage their own medical data and coordinate between providers. Although it is a national priority to make it possible to transfer patient data between systems, a variety of barriers — technological, financial and privacy-related — are slowing progress.

Drs. Ancker and Kaushal believe that people will be healthier only when everyone has access to real-time electronic healthcare information, which can be easily shared between providers. But proving that these technologies will improve outcomes isn't easy, in part because they're still relatively new and their use remains variable. Yet that's exactly what Dr. Kaushal is trying to do. While she calls the ubiquitous adoption of electronic records "inevitable," she stresses that the current reliance on systems that don't seamlessly communicate with one another — including the use of paperwork, phones, and fax machines — puts patients at risk. Because doctors in large, well-funded practices and urban or suburban areas are more likely to have electronic records that are interoperable than those who are in rural areas or serve poor populations, a digital divide might develop that further widens the healthcare gap between haves and have nots, Dr. Kaushal wrote in in June. Weaker communication between providers and less reliable documentation of test results and clinical observations, which are also more common when electronic systems aren't interoperable, are also of concern.

Looking ahead, both Drs. Ancker and Kaushal say that compensating providers for adopting electronic systems, improving interfaces to make them more useful to doctors, making systems interoperable among providers, and getting patients up to speed with how to access their health information is key to improving care. When it comes to numbers, like Gawrys's hemoglobin A1C or cholesterol stats, patient portals might include a picture or illustration along with the figure instead of a simple graph. The good news is they are optimistic that improvements like these will soon come to pass. "If I had a crystal ball, my expectation is that in 10 years we will be viewing healthcare much like other industries, including banking and travel," Dr. Ancker says. "We'll expect information to be electronic — and for our providers to have it all available to us, wherever we are."

Agents of Change

Healthcare policy researchers aim to improve the system from a variety of fronts

Research Network: Big Data at Work

Dr. Rainu Kaushal, who has twin toddlers at home, calls it her "third baby": the New York City Clinical Data Research Network. With more than $15 million to date from the independent, nonprofit Patient-Centered Outcomes Research Institute, which was created under the Affordable Care Act, the network connects six academic medical centers and 16 other organizations in New York City, bringing together 40 million medical encounters on more than 4 million unique patients to advance patient-centered research and knowledge about specific diseases and conditions, as well as to improve health systems.

"When it comes to research, being patient-centered means not only developing studies that are important and interesting, but within those studies, allowing patients to guide the specific questions that you ask," Dr. Kaushal says. Among those the New York City group is trying to answer: how a person's neighborhood affects their glucose control and health; how factors like energy level and emotional well-being are affected by bariatric surgery; and how cystic fibrosis patients use social media to communicate.

Outside researchers, too, will be able to query the NYC-CDRN for use of this data, stored at the New York Genome Center. But to gain access, they'll need to demonstrate that the work will focus on the needs of patients at every step of the process. "The research studies that we approve must be interesting to investigators and also to patients," Dr. Kaushal says. "For this reason, among others, I believe it is going to change the landscape of research and healthcare delivery."

National Policy: Theory Meets Practice

One of the department's investigators approaches his research from a powerful perspective: that of a veteran doctor. Dr. Larry Casalino, the Livingston Farrand Professor of Public Health and Chief of the department's Division of Healthcare Policy and Economics, was a family physician in full-time private practice for twenty years. "Those years help me to understand the perspectives of community-based physicians — the problems they face and the joys of patient care they experience," he says. "This helps me to frame important questions for research."

Dr. Casalino's work focuses on how the United States can improve the way healthcare is funded and organized, issues addressed heavily in the Affordable Care Act. He has written editorials in high- impact medical journals like the New England Journal of Medicine on such topics as the Center for Medicare and Medicaid Innovation (created and funded with $10 billion by the Affordable Care Act) and Accountable Care Organizations (ACOs), which make it easier for doctors and hospitals to provide coordinated, high-quality care to Medicare patients. ACOs and creative initiatives from the Innovation Center, Dr. Casalino says, could change the lives of thousands of doctors, tens of thousands of healthcare workers, and millions of patients.

Individual Patient Decisions: Comparing Costs

"If we had a way of figuring out how to match each patient with the right medication, we'd have better outcomes," notes Dr. Bruce Schackman, the Saul P. Steinberg Distinguished Professor of Psychiatry and Public Health and a professor of healthcare policy and research. "But once we have this information, how do we determine if the value of that better treatment is worth the money that society spends on it? Those are the questions that I'm interested in addressing."

Most recently, Dr. Schackman's work has resulted in funding for a major project: CHERISH (Center for Health Economics of Treatment Interventions for Substance Use Disorder, HCV and HIV). The multi-institution effort, announced in August, seeks to address a stark disparity: although a 2013 tally found that an estimated 7.6 million Americans ages 12 or older needed drug abuse treatment, only 1.5 million received it. Why? The most common reason was lack of insurance coverage and an inability to afford the costs.

With $5.8 million from the National Institute on Drug Abuse, CHERISH aims to serve as a nationwide resource for health economics research on substance use by developing and disseminating evidence that informs policy on drug treatment, as well as on hepatitis C and HIV care for substance users. To that end, it will foster collaboration among researchers, administer pilot grants, and conduct training and outreach for policymakers.

Precision Medicine: Harnessing Genomic Data

Dr. Jyotishman Pathak, who came to Weill Cornell Medicine in October from the Mayo Clinic, is focused on making big changes to what's inside each patient's personal electronic health records. In addition to the typical clinical data — weight, medical history, lab test results, and the like — the chief of the Division of Health Informatics is working to incorporate individualized genomic information so that physicians can make smarter decisions about the drugs, doses, and other interventions that they prescribe. "If both you and I are diagnosed with a certain disease, say cancer, it is quite likely that our response to existing therapies will vary due to our underlying genetics," says Dr. Pathak, who has more than $8 million in National Institutes of Health support for multiple projects to study the implementation of pharmacogenomics using electronic health records. "And it shouldn't just be about asking whether a patient will respond to one treatment over another, but also understanding the appropriate dosing regimen to increase drug efficacy and minimize the risk of side effects. I firmly believe that informatics has a crucial role to play in achieving this ambitious goal of implementing precision medicine for routine clinical care."

Ideally, Dr. Pathak would like to have everyone's genetic information incorporated into their health records as soon as possible, but he knows that the technology is still too expensive for that to be a reality. There are additional challenges around managing this "real" big data, he says, including security and ethical concerns. Certain groups, though — including those at an increased risk for cancer, heart failure, and some rare diseases — might benefit the most from the incorporation of genomic data within electronic health records for personalized clinical decision-making. Further, he says, the availability of such massive amounts of data on individual patients could help investigators and computational scientists build smarter prediction models and risk profiles — which could ultimately lead to better healthcare for everyone.

This story first appeared in Weill Cornell Medicine, Vol. 15, No.1.

A two-pronged approach offers new insights into HIV

Among the researchers contributing to the revolution is Dr. Scott Blanchard, associate director of the Tri-Institutional Chemical Biology Program, whose lab utilizes such single-molecule imaging techniques to gain further insight into complex, ever-changing biological processes. "It's much easier to simplify your understanding of a system when you watch one molecule at a time, rather than billions at a time," explains Dr. Blanchard, an associate professor of physiology and biophysics. "If you're looking at many of them, it's like trying to listen to a conversation with a billion people talking at once."It's been dubbed the "super-resolution revolution": the development of biomedical imaging tools strong enough to see individual molecules — units so miniscule, they're smaller than the wavelength of light. Such technologies are transforming the way scientists look at living cells, examining the tiniest molecular details in the search for new disease-fighting treatments.

In two parallel studies published last fall in Science and Nature, Dr. Blanchard and his colleagues revealed how they modified this super-resolution technology to track — for the first time — the precise movements of proteins on the surface of the human immunodeficiency virus (HIV). They were also able to use a method known as X-ray crystallography to determine the 3D structure of one of those proteins. Together, these discoveries could help researchers find a way to prevent HIV infection, stemming an epidemic that the WHO estimated has affected 78 million people worldwide.

For the Science study, Dr. Blanchard's group adapted single-molecule fluorescence resonance energy transfer (smFRET) imaging — an approach that uses fluorescence to measure distance on an atomic scale — to analyze the behavior of HIV. The team designed special long-lasting fluorescent molecules, or fluorophores, which were inserted into proteins on the virus's outer coating, known as envelope proteins. These glowing beacons, in conjunction with the imaging system, allowed them to visualize how the molecules moved over time, as the virus proteins changed shape.

This was important because the envelope consists of multiple proteins, referred to as trimers, that blossom like a flower when HIV comes in contact with immune cells carrying CD4 receptors, which the virus uses to enter the cell. There are 10 to 20 trimers on the surface of each HIV particle, which quickly mutate, making it hard for the body to combat the disease — and challenging researchers working to develop a vaccine. "One of the problems with HIV," says Dr. Blanchard, "is that the rate of infection and mutation is faster than your immune system can keep up."

Scientists long thought that the trimers remain passive when CD4 isn't present. But Dr. Blanchard's group found that the envelope proteins constantly shape shift, or "dance" — even without CD4. Even more striking, he and his colleagues showed that the introduction of certain antibodies stopped the envelope from opening, thereby lowering the infection rate. Tests with a small-molecule drug under development by Bristol-Meyers Squibb to prevent HIV produced similar results. "Now we know the rule — or at least, we have a hint of the rule — on how to inhibit the virus," Dr. Blanchard says. In other words, these findings could aid pharmaceutical companies in screening for more effective medications in the future, by providing a better "road map" of the virus. "If you're driving cross-country in a car but you don't have a compass or any understanding of which way is west or east, it's really difficult," he says. "We think that our approach is going to make the search for therapeutic interventions more directed."

In the other study, outlined in Nature, researchers turned to X-ray crystallography in an attempt to take a high-resolution picture of an HIV protein, with the goal of obtaining additional data about the virus's biological makeup. However, the procedure couldn't work if the molecule remained dynamic; as Dr. Blanchard puts it, "The nemesis of crystallography is movement." To freeze that molecule's actions, the team employed the same antibodies that were used in the Science study to keep the envelope protein closed.

To Dr. Harel Weinstein — the Maxwell M. Upson Professor of Physiology, chair of the Department of Physiology and Biophysics, and director of the Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine — the combination of these two technologies is what makes Dr. Blanchard's endeavors extraordinary. Not only do scientists now have concrete information about the structure of HIV molecules, he notes, they know exactly how they change when different proteins in the virus interact. And that knowledge could have benefits beyond HIV, pointing the way toward improved therapies for cancer and other illnesses. "The idea," says Dr. Weinstein, "is that it's only at this detailed level that we can hope to get cures."

— Heather Salerno

Upwards of a million more people have been infected with the hepatitis C virus (HCV) than current estimates indicate, according to new research from Weill Cornell Medicine. The investigators say their finding exposes a critical flaw in the survey that calculates disease prevalence, and underscores the need for stronger public health policies to combat the viral infection.

The study, published online Aug. 25 in Hepatology, examined the National Health and Nutrition Examination Survey (NHANES), a government survey designed to assess the health of a representative sample of the country's population. In a 2014 report, the most recent one available, the survey estimated that 3.6 million people have HCV antibodies (meaning they have been infected, but might have fought off the virus on their own), of whom 2.7 million are currently infected.

But a closer analysis revealed that the report excludes six populations, some of which are stigmatized and marginalized, yet critically in need of public health resources: people who are homeless or hospitalized, prisoners, military personnel, nursing home residents, and residents of Native American reservations. Including these groups, the researchers estimate that 4.6 million people have antibodies for HCV and that 3.5 million are infected — and even those figures likely underestimate the disease's prevalence. It is nearly impossible to assess disease prevalence in populations like the homeless with complete accuracy.

"The populations that are uncounted in the national numbers are very disadvantaged populations, so not only do we miss the magnitude of the problem, but we also don't see how much more concentrated these problems are in people affected by economic disadvantage, ethnic discrimination, and challenges accessing care," said first author Dr. Brian Edlin, an associate professor of medicine at Weill Cornell Medicine.

"We need to pay more attention to our research and surveillance of these populations, and find effective methods for reaching them and engaging them in the process of overcoming the health challenges that they face."

The scientists obtained their data from publicly available records from hospital and prison databases, among others. They then multiplied the number of people in the institutions by the prevalence of HCV reported in the literature. An accurate estimate of hepatitis C and other diseases is important for many reasons, such as assessing the mortality rate of the disease and its financial burden on the healthcare system, designing targeted public health interventions, allocating resources, and implementing treatment plans.

Interventions such as outreach, education, testing, counseling, and especially needle exchange and other syringe access programs are vital for helping people who use drugs that contain bloodborne viral disease epidemics, such as HIV and hepatitis C, in their communities, Dr. Edlin said. He noted that these initiatives have proven very successful at decreasing and managing HIV, for example. But more funding is needed to establish hepatitis C public health initiatives, such as disease tracking, prevention, treatment, and research.

"Now that we have effective treatment for hepatitis C," Dr. Edlin said, "antiviral treatment needs to be delivered to the populations most severely affected by the disease."

"With a more accurate estimate we'd be able to direct resources to create programs to address the needs," he said. "Knowing the numbers doesn't accomplish anything by itself. The numbers have to be used."

How much money would be saved if one high-risk person was prevented from contracting HIV in the United States? A new study led by a researcher at Weill Cornell Medical College and published online on Feb. 24 in Medical Care, answers this question: from $229,800 to $338,400, depending on the continuity of treatment.

The researchers projected these amounts by estimating the lifetime medical costs in people both with and without HIV, assuming that the HIV-infection occurred at age 35. The study's results, which will be presented on Feb. 25 at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Wash., will be used by fiscal planners and public health advocates as they evaluate current prevention programs and make decisions about resource allocation. One relatively new — and expensive — HIV prevention option is Pre-exposure Prophylaxis (PrEP), which is targeted at high-risk individuals and uses a medication that is also part of some HIV treatment regimens.

"This study shows the continued value of HIV prevention, even in an era when people effectively treated with HIV medications can have a close-to-normal life expectancy," said Dr. Bruce Schackman, the Saul P. Steinberg Distinguished Professor of Psychiatry and Public Health at Weill Cornell Medical College and lead author of the study. "There is still significant value in avoiding infection, from both cost and quality of life points of view."

"Recently, there has been an increased focus on new HIV prevention approaches," continued Dr. Schackman, who is also a professor of healthcare policy and research and a professor of healthcare policy and research in medicine. "That focus on prevention approaches, including the use of PrEP, led to our interest in determining the value of preventing an HIV infection."

In a 2006 study on the same topic, Dr. Schackman's team found that the lifetime medical cost of care for people with HIV, beginning at the time of infection, was $361,400 in today's dollars. While that finding was seen as a benchmark for evaluating HIV treatment and prevention, updated estimates revealed that the costs differ depending on when people with HIV enter treatment and how consistently they stay in treatment. After subtracting medical costs that the authors projected would have occurred anyway without HIV infection, the potential savings are lower than the previous estimate. This is because people with HIV are now living longer and have many of the same medical care costs as people without HIV.

To reach the new figures, the study team, including researchers from Brigham and Women's and Massachusetts General Hospital in Boston and Johns Hopkins School of Medicine and the U.S. Agency for Healthcare Research and Quality, used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model coupled with the data from the HIV Research Network (HIVRN) to project life expectancy and costs among HIV-infected persons in the U.S.

The new study consists of two types of analyses: a base case and sensitivity analyses, all tracking individuals from the age of 35 until death. The base case represents current care patterns, where patients often don't enter care as soon as they become infected and don't always follow their treatment regimens consistently or are lost from care. The sensitivity analyses, on the other hand, include a best-case scenario in which the infected individual receives antiretroviral therapy immediately and is never lost from care.

The base case resulted in a lifetime medical cost with HIV of $326,500. The best-case scenario found a lifetime medical cost with HIV of $435,200. The average lifetime medical cost for similar people without HIV was estimated at $96,700.

"Effective treatments have increased life expectancy after HIV infection to levels near those of non-infected individuals," noted Dr. Kelly Gebo, a co-senior author of the study and a professor of medicine and public health and the vice provost for education at Johns Hopkins University. "In fact, deaths from non-AIDS-related causes now exceed deaths from AIDS for those with HIV in the United States."

"As treatments becomes more effective, people with HIV will stay on them and live longer, thereby incurring greater medical costs," said another co-senior author, Dr. Elena Losina, a professor of orthopedic surgery at Harvard Medical School and an associate professor of biostatistics at the Boston University School of Public Health. "The more effective the treatment is, the greater the medical cost saving is for preventing the disease in the first place."

Studies in Both Science and Nature Provide Key Insights into the Biology of the Virus

NEW YORK (October 8, 2014) — Researchers at Weill Cornell Medical College have developed technologies that allow investigators, for the first time, to watch what they call the "dance" of HIV proteins on the virus’ surface, which may contribute to how it infects human immune cells. Their discovery is described in the Oct. 8 issue of Science, and is also a part of a study published the same day in Nature.

The new technology platform opens new possibilities for devising an approach to prevent HIV infection, says Dr. Scott Blanchard, an associate professor of physiology and biophysics at Weill Cornell, and one of three co-lead authors on the Science study. He is also an author on the Nature paper that describes a three-dimensional structure of one of the shapes, or conformations of the HIV protein.

"Making the movements of HIV visible so that we can follow, in real time, how surface proteins on the virus behave will hopefully tell us what we need to know to prevent fusion with human cells — if you can prevent viral entry of HIV into immune cells, you have won," says Dr. Blanchard, who is also associate director of Weill Cornell's chemical biology program.

"What we have shown in the Science study is that we now have the means to obtain real-time images of processes happening on the surface of intact HIV particles, which we now plan to use to screen the impact of drugs and antibodies that can shut it down," he says.

"We desperately need solutions to prevent HIV infection, which, to date, has infected or killed more than 70 million people worldwide," Dr. Blanchard says.

If this technology proves useful in HIV management, it could potentially be used to decode infection processes for other viruses, he says.

Using light to watch HIV dance

In the Science study, Dr. Blanchard worked with Dr. Walther Mothes, a HIV specialist at the Yale University School of Medicine, and with Dr. James Munro, who was Dr. Blanchard's first graduate student and who is now an assistant professor at Tufts University School of Medicine. Drs. Mothes and Munro are the two other co-lead investigators.

Dr. Blanchard adapted an imaging technique that uses fluorescence to measure distance on molecular scale — single-molecule fluorescence resonance energy transfer (smFRET) imaging — to study viral particles. His group developed fluorescent molecules (fluorophores) — which he dubs "beacons" — and the team inserted them into the virus's outer covering, known as the envelope. With two of these special beacons in place, smFRET imaging can be used to visualize how the molecules move over time, when the virus proteins change conformation. The approach provides a measure of distances, on the order of a billionth of an inch, between two beacons glowing in different colors, and this can be used to detect shape shifting as it occurs and the attached beacons move.

The team used the technology to study motions of proteins on the surface of the HIV virus (called envelope proteins) that are key to the virus's ability to infect human immune cells carrying CD4 receptor proteins. (CD4 receptor proteins help HIV bind to a cell.) The envelope consists of three gp120 and gp41 proteins positioned close together, and referred to as “trimers,” that open up like a flower in the presence of CD4, exposing the gp41 subunit that is essential for subsequent aspects of the mechanism that causes infection.

"There are 10-20 such envelope trimers on the surface of each HIV particle, and they mutate rapidly, thereby evading typical immune responses. This is why it is so difficult for humans to mount an effective immune response and why it is challenging for researchers to develop vaccines targeting the HIV envelope proteins," Dr. Blanchard says. The researchers were able to study proteins from two different strains of HIV, which contained beacons that did not alter the biology of the particles.

Then they watched.

They saw that the gp120 proteins' virus particles changed shape constantly and that the timing and nature of their movements were both similar and distinct. "This answered the first big question of how opening of the envelope trimer is triggered," Dr. Blanchard says. "Many scientists believe that the particles remain in one conformation until they come across a CD4-positive cell. But we saw that the proteins dance when no CD4 was present — they change shape all the time."

The researchers were then able to watch how the viruses responded when synthetic CD4 was introduced. They also saw that antibodies known to exhibit some effectiveness acted to prevent gp120 from opening, and that these effects correlated with a decrease in the virus' ability to infect cells. Similar things happened when they introduced a small molecule now under development to prevent HIV infection.

"The practical outcome from this technology is that we can begin to understand how the biological system moves. So far we have detected three different conformations of the envelope trimer. We are working now to improve the technology to achieve the imaging precision we need to make broadly effective therapies," Blanchard says.

Technologies work hand in hand

The Nature study, led by researchers at the National Institute of Allergy and Infectious Diseases, used X-ray crystallography to capture a three-dimensional structure of one of the conformations revealed in the Science paper. The protein constructs used in this investigation were originally developed by a team of researchers headed by Dr. John Moore, professor of microbiology and immunology at Weill Cornell.

"The antibodies used in the crystallography study are ones that we observed to stop the dance of the HIV envelope proteins, pushing the trimer assembly into a quiescent, ground state," Dr. Blanchard says.

"This concrete, atomic resolution picture of what the pre-fusion machinery looks like and where these antibodies bind provides an important step forward to understanding HIV's biology," he says.

"Dr. Blanchard believes both techniques — smFRET and X-ray crystallography — can work hand in hand to help scientists describe the functions of molecules from the perspective motion, including the other two distinct conformations identified in the smFRET study.

"The approach is really a breakthrough for science because most research is done in a test tube where billions of molecules are present, all behaving independently. It is very difficult to extract direct information about these types of movements from indirect observations," such as those that don't use imaging technology, he says. "The single-molecule approach allows practical, interpretable, real-time information to be obtained about molecular processes in complex biological systems."

This work was supported by NIH grants R21 AI100696, P01 56550, and R01 GM098859, by the Irvington Fellows Program of the Cancer Research Institute, a fellowship from the China Scholarship Council-Yale World Scholars, grants from the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Consortium, the NIH Intramural Research Program (Vaccine Research Center), the Bill & Melinda Gates Foundation and the United States Agency for International Development (USAID).

Support for the Nature study was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, and by grants from the Division of AIDS, NIAID, National Institutes of Health for CHAVI and CHAVI-Immunogen Discovery Centers, from the National Institutes of General Medical Sciences, from the Irvington Fellows Program of the Cancer Research Program, and from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.

Contributing to the Science study were Xiaochu Ma (Yale University School of Medicine), Jason Gorman, Peter D. Kwong and James Arthos (National Institute of Allergy and Infectious Diseases), Zhou Zhou (Weill Cornell Medical College), Dennis R. Burton (The Scripps Research Institute), Wayne C. Koff (International AIDS Vaccine Initiative), Joel R. Courter and Amos B. Smith III (the University of Pennsylvania).

Co-authors of the Nature study are Peter D. Kwong, Marie Pancera, Tongqing Zhou, Aliaksandr Druz, Ivelin S. Georgiev, Cinque Soto, Jason Gorman, Priyamvada Acharya, Gwo-Yu Chuang, Gilad Ofek, Guillaume B. E. Stewart-Jones, Jonathan Stuckey, Robert T. Bailer, M. Gordon Joyce, Mark K. Louder, Yongping Yang, Baoshan Zhang, and John R. Mascola (National Institute of Allergy and Infectious Diseases), Jinghe Huang, Mark Connors, Nancy Tumba and Lynn Morris (National Institute of Allergy and Infectious Diseases), Myron S. Cohen (National Institute for Communicable Diseases of the National Health Laboratory Service, South Africa), Barton F. Haynes (Duke University), James B. Munro and Walther Mothes (Yale University School of Medicine).

Technologies invented in the Blanchard lab have been licensed to the Lumidyne Corporation.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain- injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

Six Weill Cornell scientists have been selected as winners of the Daedalus Fund for Innovation, a new medical college program that helps advance promising early-stage applied and translational research that has commercial potential.

The investigators, Drs. Peter Goldstein, Gang Lin, David Lyden, Stefano Rivella, Enrique Rodriguez-Boulan and Vladislav Sandler will each receive up to $100,000 one-year grants that fund studies demonstrating that their early-stage discoveries can be translated into effective treatments for patients. An independent advisory committee comprised of a Weill Cornell faculty member and experts from the biopharmaceutical and venture capital industries selected the projects from nearly 30 applications for the Daedalus Fund's first round of funding.

"The Daedalus Fund is helping us mobilize and innovate," said Larry Schlossman, managing director of BioPharma Alliances and Research Collaborations at Weill Cornell, who manages the Daedalus Fund. "That's incredibly exciting. I see so much rich opportunity in Weill Cornell's research enterprise, but some of the projects need a little help getting across the finish line or getting to the proverbial take-off point where they will be viewed favorably by industry as potential candidates for further development."

Established by Weill Cornell Dean Dr. Laurie H. Glimcher earlier this year, the Daedalus Fund is designed to help Weill Cornell investigators make their research more appealing to the biopharmaceutical industry. Investors require "proof of concept" — for instance, data derived from testing in animal models or the development of a new biomarker — as the standard by which they determine whether a project is ready for funding.

While grants from the National Institutes of Health or other agencies fund basic science research, they often don't provide enough money to cover these "proof of concept" studies. This funding gap is one of the greatest obstacles scientists face when trying to advance early-stage discoveries into next- generation treatments.

"We are extremely thankful that Weill Cornell came up with this program," said Dr. Rodriguez-Boulan, the Charles and Margaret Dyson Professor in Ophthalmology Research and a professor of cell and developmental biology, who up until now has received small, short-term grants from small foundations to investigate a new drug to treat incurable blinding diseases, such as Stargardt disease and age-related macular degeneration.

"With this grant from the Daedalus Fund, we will really be able to study the most important aspects in terms of developing drugs for human use. That means showing in animals that our drug can cure these diseases. Once you show that, you are one long step closer to a treatment in humans."

A Potential New Treatment for Nerve Pain

At least 20 million adults in the United States suffer from chronic and often intense nerve pain caused by the abnormal activation of the control system for a group of cells in the peripheral nervous system. This channel protein, known as HCN, helps regulate how neurons function and react to stimuli. While the most common treatment is one or more pain medications, none of them work particularly well and often carry risk of serious side effects including addiction.

Weill Cornell anesthesiologist Peter Goldstein and colleagues at Weill Cornell Medical College found that the general anesthetic propofol can block the activity of the protein, potentially offering relief to pain sufferers — but at a cost. Used by anesthesiologists for surgical sedation and anesthesia, propofol is too powerful a drug for use outside of an operating room setting and, if abused or misused, can be fatal. (King of Pop Michael Jackson died from an overdose.) But with this preliminary finding, supported by the Weill Cornell Department of Anesthesiology, too promising to dismiss, the collaborators dug deeper and discovered a molecule that is structurally similar to propofol — it blocks the same channel protein and provides pain relief — but lacks its sleep-inducing properties.

The Daedalus award will allow Dr. Goldstein's lab to test novel, related compounds synthesized in the lab of co-investigator Dr. Anthony Sauve, an associate professor of pharmacology at Weill Cornell, in an animal model of chronic pain to see if they have the same pain-relieving effects as propofol and the related non-anesthetic compound. If successful, Dr. Goldstein hopes at least one of them can then be developed into a new drug to treat the condition.

"This is a lifeline," said Dr. Goldstein, a professor of anesthesiology and an associate professor of medical ethics (in medicine), of the grant award. "This keeps the project going to pursue what we think is a very promising line of investigation."

Innovative Treatments for Inflammatory Bowel Disease

A few years back, Weill Cornell scientist Gang Lin designed a class of inhibitors that selectively targeted an enzyme expressed in tuberculosis. While the proteasome is also present in various forms in the human body, tuberculosis is the only known pathogenic bacterium to express it. The enzyme is critical to TB's ability to defend itself against its human host. Dr. Lin, an associate research professor of microbiology and immunology, designed drugs that inhibited the bacterium's proteasome more potently than its host's, killing the parasite while likely avoiding collateral damage in the patient.

At the time, inflammatory bowel diseases were the furthest thing from Dr. Lin's mind. Then in 2009, a paper was published in Nature Medicine describing the therapeutic potential of an immunoproteasome inhibitor in autoimmune diseases.

One form of proteasome in humans is called the immunoproteasome, which plays pivotal roles in immune responses. The 2009 paper showed that immunoproteasome selective inhibitors effectively reduced inflammation in mice that had type I diabetes and arthritis. Later research confirmed that finding, and also showed efficacy in mice with colitis, multiple sclerosis and lupus. While the inhibitors were groundbreaking in their therapeutic potency, scientists found them to be reactive, irreversible and unstable.

Taking advantage of his expertise in proteasome inhibitor design, Dr. Lin's team investigated and synthesized two classes of compounds that do not react with the immunoproteasome. Now, armed with funding from the Daedalus Fund, he will test them on mice that mimic human Crohn's disease — a common form of debilitating inflammatory bowel disease. He is working with Dr. Carl Nathan, chairman of Microbiology and Immunology and the R.A. Rees Pritchett Professor of Microbiology; Dr. Xiaojing Ma, a professor of microbiology and immunology and of microbiology and immunology in pediatrics; Dr. Jane Salmon, a professor of medicine and of medicine in obstetrics and gynecology, as well as a rheumatologist at Hospital for Special Surgery; and Dr. Franck Barrat, a professor of microbiology and immunology at Weill Cornell and a senior scientist in Hospital for Special Surgery's Autoimmunity and Inflammation Program.

"We are extremely grateful and very pleased to receive a grant from the Daedalus Fund," Dr. Lin said. "The fund really provides us an opportunity to demonstrate these compounds' efficacy and lack of toxicity in mice — a critical step in drug research and development."

A Liquid Biopsy for Cancer

Invasive needle biopsies are the only way to tell whether a patient's cancer is responding to its prescribed treatment — and oftentimes the answer comes too late. By the time oncologists learn that the treatment isn't working, likely due to a mutation causing resistance, the cancer has likely already spread.

But that may soon change. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics and of cell and developmental biology, together with Dr. Hector Peinado Selgas, an assistant professor of molecular biology in pediatrics, have developed a blood test that isolates small, spherical tumor-secreted packages containing protein, RNA and DNA from patients' bloodstreams. Cancer cells release these vesicles, known as exosomes, which use the bloodstream to travel around the body and spread the seeds for metastasis.

Dr. Lyden believes his liquid biopsy can quickly determine how effective a cancer patient's treatment is by measuring the number and content of exosomes circulating in that patient's blood, ultimately leading to personalized treatment approaches. He also hypothesizes that the test can predict future cancer metastasis. The Daedalus Fund grant will enable Dr. Lyden to characterize and analyze the protein and DNA content of tumor exosomes. Ultimately, he will use that information to develop a platform that can identify and screen patients for biomarkers in melanoma, breast and prostate cancers.

"I was pleased that the reviewers funded a project that's considered ‘out of the box,'" Dr. Lyden said. "This is a whole new cancer field in which discoveries regarding the properties of cancer vesicles have been made by a few groups of investigators including work in our laboratory. This fund is helping us overcome a lot of obstacles and accelerate our projects so we can connect with drug companies to rapidly translate our discovery into a clinical application."

Curing Blood Disorders

Transfusions offer a lifeline to children who have the blood disorders sickle cell anemia and beta-thalassemia, but they are often cumbersome and hardly a panacea. For these children, whose conditions are characterized by misshapen or too few of the oxygen-carrying molecules present in all red blood cells, their only hope for survival is bone marrow transplants.

But that, too, is fraught with risk. A bone marrow transplant requires a compatible donor — a minority of patients locate one — and a match doesn't guarantee a successful outcome.

Stefano Rivella, an associate professor of genetic medicine in pediatrics at Weill Cornell, believes that a new gene therapy technique that he's developing with collaborators may cure these conditions.

Sickle cell anemia and beta-thalassemia result from a mutation in the beta-globin gene, which is charged with producing an essential part of hemoglobin molecules that carry life-sustaining oxygen throughout the body. A piece of DNA, called the locus control region, activates the beta-globin gene after a baby is born, and shuts down a second gene, called the gamma globin gene, which is tasked with making a critical part of fetal hemoglobin when a baby is in the womb.

Dr. Rivella is investigating whether he can combine a classical gene therapy approach with an innovative technology. Using gene therapy, Dr. Rivella will insert a new and functional copy of the beta-globin gene into patient cells while also introducing a new gene that reprograms the genome in the locus control region. By reprogramming the genome, Dr. Rivella hopes to shut down the mutant beta-globin gene and reactivate the gamma globin gene, enabling the gamma globin gene to generate fetal hemoglobin, which can also sustain life. He's theorized that a genetically modified HIV virus that's been stripped of its viral properties could be used to transmit these new instructions to the genome. This approach would leave behind two healthy, therapeutic genes, while shutting down the toxic mutant gene.

The Daedalus Fund will support Dr. Rivella and his lab's efforts to develop this modified virus and test its efficacy in petri dishes using patient-donated cells.

"I cannot be more grateful to Weill Cornell, Dean Laurie Glimcher and Larry Schlossman for sponsoring our faculty's research ideas and helping us move them forward," Dr. Rivella said.

Ending Juvenile Blindness

For children born with sight, the thought of losing their vision by the time they are 30 years old is terrifying. But that's exactly what happens with children born with Stargardt disease, the most common form of inherited juvenile macular degeneration for which there is no treatment.

Some 100,000 Americans have Stargardt disease, which is characterized by a genetic mutation that enables a yellowish-brown pigment composed of mostly fats to accumulate in the eye. The pigment, known as lipofuscin, is a product of cellular wear and tear that is often found in muscle, kidney, liver, heart and nerve cells. Lipofuscin detected in the eye is particularly worrisome, says Weill Cornell cell biologist Enrique Rodriguez-Boulan. Researchers believe it to be toxic to a support cell for the light-sensitive photoreceptors cells that allow people to see, known as the retinal pigment epithelium.

Using basic science methods, Dr. Rodriguez-Boulan, the Charles and Margaret Dyson Professor in Ophthalmology Research, and collaborators Dr. Marcelo Nociari, an assistant research professor of immunology in ophthalmology, and Dr. Fred Maxfield, chairman of Biochemistry and the Vladimir Horowitz and Wanda Toscanini Horowitz Distinguished Professor in Neuroscience, discovered that the drug beta cyclodextrin can successfully bind to lipofuscin and remove it from the eye. The Daedalus Fund will enable the research team to see if the same effect is true in animal models before blindness occurs.

"So far we have been able to show that these drugs remove lipofuscin from the eye, but that's not the same as showing that we can prevent model mice from becoming blind," said Dr. Rodriguez-Boulan, also a professor of cell and developmental biology and of cell biology in ophthalmology. "We're getting a chance to go for it and try to cure the blinding disease. This is a big step forward in showing that this is eventually good for humans."

Dr. Rodriguez-Boulan hopes that his findings can be applied to age-related macular degeneration, a leading cause of vision loss among people age 65 and older that is not well understood and has no treatment. While lipofuscin accumulates dramatically in the retinal pigment epithelium with age, it's not clear if it also plays a role in this condition. Dr. Rodriguez-Boulan hopes that a successful treatment for Stargardt, where lipofuscin is a clear cause of disease, could ultimately be tested on macular degeneration patients to see if it makes a difference.

A New Bone Marrow Transplant

Search a textbook for adult hemogenic endothelial cells and one would likely come up empty. In scientific literature, these cells — which give rise to blood and enable the body to regenerate it for the duration of life — exist only during fetal development and disappear soon after birth.

But Weill Cornell biologist Vladislav Sandler is challenging conventional wisdom. After scouring blood vessels in various organs through the human body, Dr. Sandler recently spotted a small cluster of cells in an adult liver that has the same signature of these progenitor cells — including their regenerative abilities. Using advanced research techniques, Dr. Sandler, a faculty instructor at Weill Cornell who is being recruited for the Department of Medicine, demonstrated that adult hemogenic endothelial cells can reactivate and generate blood cells that closely resemble bone marrow stem cells — the building blocks of blood necessary for life. He then transplanted them into immune-deficient mice and discovered that the engineered cells were capable of regenerating the rodents' blood system, just as they do during embryonic development. The Daedalus Fund grant will allow Dr. Sandler to further test these cells in mice to determine how fast they take hold and how many are needed for successful regeneration.

If the regenerative and transplantable properties of adult hemogenic endothelial cells can be replicated in humans, the finding could benefit the millions of patients with blood disorders — thalassemia, sickle cell and other genetic diseases, blood cancers and even infections like HIV — for which the most common cure is matched bone marrow transplants. Dr. Sandler hopes that patients' own cells can be used to generate blood stem cells free of the defects that caused the original disease, and then re-transplanted into the patients' bodies to treat their conditions.

"This grant is the greatest validation to any doubts that I may have had," Dr. Sandler said. "This gives me an opportunity to check this hypothesis. And it says that Weill Cornell is interested in promoting its own people, giving them the opportunity to do something both fundamentally important for science and potentially important for patients."

DOHA, QATAR (June 17, 2014) — HIV epidemics are emerging among people who inject drugs in several countries in the Middle East and North Africa. Though HIV infection levels were historically very low in the Middle East and North Africa, substantial levels of HIV transmission and emerging HIV epidemics have been documented among people who inject drugs in at least one-third of the countries of this region, according to findings published today in PLOS Medicine.

The HIV epidemics among people who inject drugs (PWID) are recent overall, starting largely around 2003 and continuing to grow in most countries. However, they vary across the region. In countries such as Afghanistan, Bahrain, Egypt, Iran, Morocco, Oman, and Pakistan, on average between 10 and 15 percent of PWID are HIV-positive. The HIV epidemics in these countries appear to be growing; in Pakistan, for example, the fraction of PWID who are HIV-infected increased from 11 percent in 2005 to 25 percent in 2011. In Iran, the HIV epidemic among PWID has stabilized at about 15 percent. There are, however, other countries where limited HIV transmission was found among PWID, such as in Jordan, Lebanon, Palestine and Syria.

"Not only have we found a pattern of new HIV epidemics among PWID in the region, but we found also indications that there could be hidden HIV epidemics among this marginalized population in several countries with still-limited data," said Ghina Mumtaz, lead author of the study and senior epidemiologist at the Infectious Disease Epidemiology Group at Weill Cornell Medical College-Qatar. "For example in Libya, the first study among people who inject drugs was conducted only recently and unveiled alarmingly high levels of HIV infection, suggesting that the virus has been propagating, unnoticed, among this population for at least a decade. Eighty-seven percent of PWID in Tripoli, the capital of Libya, were infected with HIV, one of the highest levels reported among PWID globally."

The study estimated that there are about 626,000 people who inject drugs in the Middle East and North Africa. This translates into 24 people who inject drugs for every 1,000 adults in this part of the world. These individuals are typically involved in several types of behavior that expose them to HIV infection, such as sharing of needles or syringes, a behavior reported by 18 to 28 percent of injecting drug users during their last injection across these countries.

"The levels of HIV infection among people who inject drugs tell only half of the story. We also see high levels of risky practices that will likely expose this population to further HIV transmission in the coming years," said Dr. Laith Abu-Raddad, principal investigator of the study and associate professor of public health in the Infectious Disease Epidemiology Group at Weill Cornell Medical College-Qatar. "We found that nearly half of people who inject drugs are infected with hepatitis C virus, another infection of concern that is also transmitted though sharing of needles and syringes."

"Since the HIV epidemics among people who inject drugs in the Middle East and North Africa are still overall in an early phase, there is a window of opportunity to prevent these epidemics from further growth. This will also limit the potential for HIV transmission to be bridged to other population groups," Mumtaz said.

Although the region overall lags behind in responding to the emerging HIV epidemics among PWID, several countries have made significant progress in building and expanding harm-reduction programs and integrating them within the socio-cultural fabric of the region. These programs refer to policies and strategies aimed at reducing the harmful consequences of injecting drug use, including needle- and syringe-exchange programs and opioid-substitution therapies.

"It is of priority that countries in the region expand HIV surveillance systems among PWID to detect and monitor these budding and growing HIV epidemics. About half of the countries of the region still lack sufficient data to assess the levels of HIV infection among this population, and we continue to discover these epidemics several years after their onset. We need to be ahead of the epidemic to prevent a public health burden that this region is largely not prepared to handle," Dr. Abu-Raddad said.

About Weill Cornell Medical College in Qatar 

Weill Cornell Medical College in Qatar is a partnership between Cornell University and Qatar Foundation. It offers pre-medical and medical courses leading to the Cornell University M.D. degree with teaching by Cornell and Weill Cornell faculty and by physicians at Hamad Medical Corporation (HMC) and Aspetar Orthopedic and Sports Medicine Hospital who hold Weill Cornell appointments. Through its biomedical research program, WCMC-Q is building a sustainable research community in Qatar while advancing basic science and clinical research. Through its medical college, WCMC-Q seeks to provide the finest education possible for medical students, to improve health care both now and for future generations, and to provide high quality health care to the Qatari population.

Finding Represents a Scientific Feat and Progress Towards an HIV Vaccine

NEW YORK (October 31, 2013) — Collaborating scientists at The Scripps Research Institute (TSRI) and Weill Cornell Medical College have determined the first atomic-level structure of the tripartite HIV envelope protein — long considered one of the most difficult targets in structural biology and of great value for medical science.

The new data provide the most detailed picture yet of the AIDS-causing virus's complex envelope, including sites that future vaccines will try to mimic to elicit a protective immune response.

"Most of the prior structural studies of this envelope complex focused on individual subunits, but we've needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine," said Dr. Ian A. Wilson, the Hansen Professor of Structural Biology at TSRI and a senior author of the new research with biologists Drs. Andrew Ward and Bridget Carragher of TSRI and virologist and immunologist Dr. John Moore of Weill Cornell.

The findings were published in two papers in Science Express, the early online edition of the journal Science, on October 31, 2013.

A Difficult Target

HIV, the human immunodeficiency virus, infects about 34 million people globally, 10 percent of whom are children, according to World Health Organization estimates. Although antiviral drugs are now used to manage many HIV infections, especially in developed countries, scientists have long sought a vaccine that can prevent new infections and would help perhaps to ultimately eradicate the virus from the human population.

However, none of the HIV vaccines tested so far has come close to providing adequate protection. This failure is due largely to the challenges posed by HIV's envelope protein, known to virologists as Env.

HIV's Env is not a single, simple protein but rather a "trimer" made of three identical, loosely connected structures with a stalk-like subunit, gp41, and a cap-like region, gp120. Each trimer resembles a mushroom and about 15 of these Env trimers sprout from the membrane of a typical virus particle, ready to latch onto susceptible human cells and facilitate viral entry.

Although Env in principle is exposed to the immune system, in practice it has evolved highly effective strategies for evading immune attack. It frequently mutates its outermost "variable loop" regions, for example, and also coats its surfaces with hard-to-grip sugar molecules called glycans.

Even so, HIV vaccine designers might have succeeded by now had they been able to study the structure of the entire Env protein at atomic-scale — in particular, to fully characterize the sites where the most effective virus-neutralizing antibodies bind. But Env's structure is so complex and delicate that scientists have had great difficulty obtaining the protein in a form that is suitable for atomic-resolution imaging.

"It tends to fall apart, for example, even when it's on the surface of the virus, so to study it we have to engineer it to be more stable," said Dr. Ward, who is an assistant professor in TSRI's Department of Integrative Structural and Computational Biology.

The key goal in this area has been to engineer a version of the Env trimer that has the stability and other properties needed for atomic-resolution imaging, yet retains virtually all of the complex structural characteristics of native Env.

Imaging Env

After many years in pursuit of this goal, Drs. Moore, Rogier W. Sanders and their colleagues at Weill Cornell, working with Drs. Wilson, Ward and others at TSRI, recently managed to produce a version of the Env trimer (called BG505 SOSIP.664 gp140) that is suitable for atomic-level imaging work — and includes all of the trimer structure that normally sits outside the viral membrane. The TSRI researchers then evaluated the new Env trimer using advanced versions of two imaging methods, X-ray crystallography and electron microscopy. The X-ray crystallography study was the first ever of an Env trimer, and both methods resolved the trimer structure to a finer level of detail than has been reported before.

"The new data are consistent with the findings on Env subunits over the last 15 years, but also have enabled us to explain many prior observations about HIV in structural terms for the first time," said Dr. Jean-Philippe Julien, a senior research associate in the Wilson laboratory at TSRI, who was first author of the X-ray crystallography study.

The data illuminated the complex process by which the Env trimer assembles and later undergoes radical shape changes during infection and clarified how it compares to envelope proteins on other dangerous viruses, such as flu and Ebola.

Arguably the most important implications of the new findings are for HIV vaccine design. In both of the new studies, Env trimers were imaged while bound to broadly neutralizing antibodies against HIV. Such antibodies, isolated from naturally infected patients, are the very rare ones that somehow bind to Env in a way that blocks the infectivity of a high proportion of HIV strains.

Ideally an HIV vaccine would elicit large numbers of such antibodies from patients, and to achieve that, vaccine designers would like to know the precise structural details of the sites where these antibodies bind to the virus — so that they can mimic those viral "epitopes" with the vaccine.

"It's been a privilege for us to work with the Scripps' team on this project," said Dr. Moore, a professor of microbiology and immunology at Weill Cornell. "Now we all need to harness this new knowledge to design and test next-generation trimers and see if we can induce the broadly active neutralizing antibodies that an effective vaccine is going to need."

"One surprise from this study was the revelation of the complexity and the relative inaccessibility of these neutralizing epitopes," Dr. Julien added. "It helps to know this for future vaccine design, but it also makes it clear why previous structure-based HIV vaccines have had so little success."

"We found that these neutralizing epitopes encompass features such as the variable loop regions and glycans that were excluded from previous studies of individual Env subunits," said Dmitry Lyumkis, first author of the electron microscopy study, who is a graduate student at TSRI participating in the NIH-funded National Resource for Automated Molecular Microscopy. "We observed, too, that neutralizing antibody binding to gp120 can be influenced by the neighboring gp120 structure within the trimer — another complication that was not apparent when we were not studying the whole trimer."

Having provided these valuable structural insights, the new Env trimer is now being put to work in vaccine development. "We and others are already injecting the trimer into animals to elicit antibodies," Dr. Ward said. "We can look at the antibodies that are generated and if necessary modify the Env trimer structure and try again. In this iterative way, we aim to refine and increase the antibody response in the animals and eventually, humans."

Other contributors to the studies, "Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 Env trimer," and "Crystal structure of a soluble cleaved HIV-1 envelope trimer in complex with a glycan-dependent broadly neutralizing antibody," included TSRI's Natalia de Val, Devin Sok, Drs. Robyn L. Stanfield and Marc C. Deller; and Weill Cornell Medical College's Albert Cupo and Dr. Per-Johan Klasse. In addition to Drs. Wilson, Ward and Carragher, senior participants at TSRI included Drs. Clinton S. Potter and Dennis Burton.

The research was supported in part by the National Institutes of Health (HIVRAD P01 AI82362, R01 AI36082, R01 AI084817, R37 AI36082, R01 AI33292), the NIH's National Institute of General Medical Sciences (GM103310) and the International AIDS Vaccine Initiative Neutralizing Antibody Consortium. IAVI has filed a patent that includes WCMC and TSRI authors on the development of the BG505 SOSIP.664 trimers as vaccine antigens.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.