UCSF moves ahead with plans for new General Hospital research facility

SFGH building would support long-standing partnership, catalyze research progress.

In addition to being the city's safety-net hospital and a premier trauma center, San Francisco General Hospital is home to breakthrough research by UCSF scientists. (Photo by Steve Babuljak)

By Kate Vidinsky, UC San Francisco

It has been more than a decade since a baby was born HIV-positive in San Francisco.

This is no small feat, considering transmission of the disease from untreated HIV-positive mothers to their children used to occur in one of every four cases.

Thanks in large part to groundbreaking research from the unique partnership between UC San Francisco and San Francisco General Hospital and Trauma Center (SFGH), researchers are now focused on finding a cure for HIV, a disease that first emerged as an almost certain death sentence.

“The roots of the remarkable progress in HIV medicine over the last three decades can be traced to the partnership between UCSF and SFGH,” said Diane Havlir, M.D., a UCSF professor of medicine and chief of the HIV/AIDS Division at SFGH.

“Thanks to these efforts, we are now talking about curing HIV and aging in HIV – topics we never imagined, even a decade ago.”

The newly constructed San Francisco General Hospital and Trauma Center will open in 2015, providing an updated place to treat the city’s population. In line with these efforts to renew and refresh the SFGH campus, UCSF is hoping to to construct a new UCSF research building at SFGH.

The building would provide modern research facilities, centralize the research efforts that are currently spread throughout nine buildings at SFGH, and allow UCSF to comply with University of California seismic policies. It would house many research centers, affiliated programs and major labs that are dedicated to improving the health of the SFGH patient population and individuals worldwide.

“Our HIV researchers are recognized internationally for their collaborative approach, community involvement and close ties to the San Francisco Department of Public Health,” Havlir said. “A new UCSF research building at SFGH will bring together teams from different disciplines under one roof and undoubtedly catalyze progress for all its tenants.”

Historic partnership

The mutually beneficial partnership dates back to 1864, when Toland Medical College opened across the street from San Francisco’s county hospital to provide clinical training for doctors serving the citizens of the booming Gold Rush city.

For more than 140 years, the offspring of those two entities – UCSF and SFGH – have worked together to provide the best care for some of the city’s most vulnerable patients. Long recognized as San Francisco’s public safety-net hospital, SFGH provides primary, specialty and hospital care to everyone in San Francisco, regardless of their ability to pay.

The hospital also is home to the city’s only trauma center.

Nearly 2,000 UCSF physicians and staff work side-by-side at SFGH with 3,500 employees of the San Francisco Department of Public Health.

In addition to being an essential training site for UCSF physician residents, SFGH is a major research site for UCSF. The hospital receives about $150 million in research grants each year, which accounts for a quarter of all National Institutes of Health grants awarded to UCSF.

“Many of our clinicians are physician-scientists and do research dedicated to the needs of our patients. Their discoveries improve the health of our city and impact health worldwide,” said Sue Carlisle, Ph.D., M.D., vice dean of the UCSF School of Medicine.

Applying the research to benefit patients

Each year, more than 4,000 cases are treated in the SFGH Level 1 trauma center. Of those, about 1,100 involve some sort of musculoskeletal injury – usually resulting from car or motorcycle accidents, or a fall – and more than 200 are admitted for orthopedic surgery.

According to Theodore Miclau, M.D., chief of orthopaedic surgery at SFGH, research informs every aspect of his clinical practice.

“We incorporate a research component into everything we do and focus on translational problems that directly benefit our own patients, while paving the way internationally,” he said.

Miclau’s team has adopted a true bench-to-bedside approach that encompasses every aspect of orthopaedic research – from molecular biology and biomechanics lab work to traditional clinical and procedure-based studies. By examining how bones heal at the molecular and cellular levels, UCSF experts are developing new therapeutic strategies to make bones heal faster and then offering those therapies to patients at the hospital.

Building for the future

UCSF’s research programs at SFGH are currently housed in several buildings at SFGH, including the historic brick buildings that line Potrero Avenue.

These buildings no longer meet UC’s seismic safety standards and UCSF’s research operations must be relocated by October 2019.

The proposed site for the new research building is the parking lot adjacent to 23rd Street. Approximately 800 UCSF employees will work in the new building, including 200 UCSF physician-scientists and clinicians.

Earlier this month, San Francisco’s Health Commission unanimously approved a resolution supporting the first step in the approval process – a non-binding term sheet. The Board of Supervisors will consider the proposal in June.

Following approval by the San Francisco Board of Supervisors and the UC Board of Regents, UCSF will complete an environmental impact review (EIR). After completion of the EIR, it is anticipated that negotiations on the ground lease will be finalized and approvals sought by the Board of Supervisors and Board of Regents in spring/summer 2016.

“What makes our work successful isn’t the individual or the place. It’s the team,” Miclau said. “Having a new research building is critical because it keeps researchers and surgeons co-located. The ability to easily collaborate with others will help translate our findings in truly meaningful ways for our patients, which in the end is what we all ultimately strive for.”

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Binational police program in Tijuana targets HIV reduction

Effort also aims to improve safety of officers.

binational team from UC San Diego and the U.S.-Mexico Border Health Commission, Mexico Section, will train Tijuana law enforcement officers on needle handling and HIV prevention.

By Heather Buschman, UC San Diego

Research consistently shows that policing practices, such as confiscating or breaking needles, are key factors in the HIV epidemic among persons who inject drugs. Police officers themselves are also at risk of acquiring HIV or viral hepatitis if they experience needle-stick injuries on the job — a significant source of anxiety and staff turnover.

A binational team from the UC San Diego School of Medicine and the U.S.-Mexico Border Health Commission, Mexico Section, has launched a new research project aimed at promoting prevention of HIV and other blood-borne infections. The effort is led by Steffanie Strathdee, Ph.D., professor and director of the UC San Diego Global Health Initiative; Leo Beletsky, J.D., M.P.H., associate professor; and Gudelia Rangel, Ph.D., deputy general director for migrant health and executive secretary of the Mexico Section of the Mexico-United States Border Health Commission, in partnership with the Tijuana Police Department and Police Academy. The binational team will offer and evaluate Proyecto ESCUDO (Project SHIELD), a police education program designed to align law enforcement and HIV prevention in Tijuana.

“Our unprecedented partnership with the Tijuana police department enables us to evaluate ESCUDO as a binational effort,” said Strathdee, who is also associate dean of global health sciences and chief of the Division of Global Public Health at UC San Diego’s Department of Medicine.

“Research by our team and others shows that police practices are fueling HIV risks among drug users,” noted Rangel. “This project serves a dual purpose by aiming to reduce the risk of blood-borne infections among the police and people who inject drugs in the community.”

Proyecto ESCUDO will monitor trends in occupational needle-sticks and the attitudes, behaviors and safety precautions taken by Tijuana police. ESCUDO’s impact on people who inject drugs will be externally validated through a parallel study of Tijuana drug injectors.

“We are very excited by this unique partnership,” said Secretario Alejandro Lares, Tijuana’s chief of police. “Proyecto ESCUDO will be the first study of its kind in the world.”

“These findings are expected to inform future international efforts to bring police education programs to scale in the growing number of countries where policing is a documented driver of HIV infection,” said Beletsky, an associate professor of law and public health at UC San Diego and at Northeastern University.

Funding support for this project comes from the UC San Diego Center for AIDS Research, Open Society Foundations and National Institute on Drug Abuse (grant R01DA039073).

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Microclinics help keep Kenyan HIV patients in care

Activating patients’ existing social networks reduces stigma.

A community meeting to support HIV/AIDS health services for FACES (Family AIDS Care and Education Services), a joint program of UCSF and the Kenya Medical Research Institute. (Photo by Rachel Burger)

By Jeff Sheehy, UC San Francisco

A team led by researchers from UC San Francisco, Organic Health Response and Microclinic International is reporting results of a study that showed significant benefits of microclinics – an innovative intervention that mobilized rural Kenyan HIV patients’ informal social networks to support their staying in care.

The results showed that microclinics cut in half the normal rate of disengagement from care, which was defined as missing a clinic appointment by 90 days or more, when compared to the control group, and reduced the perceived stigma of HIV by 25 percent within the larger community.

“When HIV patients fall out of care, they lose access to their medications, and untreated HIV patients will eventually develop AIDS. Keeping patients in care is not only a challenge in resource limited settings, but even in the U.S. where the CDC estimates that only 40 percent of HIV patients are regularly engaged in care,” said the study’s lead author, Matthew D. Hickey, a graduating UCSF medical student who will be starting residency in UCSF’s internal medicine/primary care program at San Francisco General Hospital and Trauma Center.

“Microclinics are a novel approach in solving this problem, he said, “in large part because they directly and innovatively address the issue of stigma.”

The research is available starting May 12 online ahead of print in the Journal of Acquired Immune Deficiency Syndromes.

The intervention took place on Mfangano Island in Lake Victoria, which is surrounded by the countries of Uganda, Kenya and Tanzania. The island has a population of about 21,000 living in small villages of 500 to 1,500 people. Almost 30 percent of the population is HIV infected. FACES (Family AIDS Care and Education Services), a joint program of UCSF and the Kenya Medical Research Institute, has been supporting HIV care, treatment and prevention in western Kenya, including the island, in collaboration with the Kenya Ministry of Health since 2004.

FACES researchers and clinicians partnered with Microclinic International and the Organic Health Response to assess whether its social network model would help retain HIV patients in care. The Microclinic Social Network Model works with individuals and communities to identify existing social networks and use those to address wide spread and deadly diseases in communities. The Organic Health Response coordinates a solar-powered community center on Mfangano Island that served as the headquarters for this intervention.

“The rural communities on Mfangano Island where we are working have tremendous stores of social capital.  People help each other when an individual or family is in need. If someone gets sick or injured, needs help farming or getting together the money for school fees, friends and family pitch in to help. But, that often was not true when the need was due to HIV. For example, a breadwinner became sick with AIDS and everyone knew what was going on, but no one talked about it. He fell through the cracks of his social network and, without support, he was lost to care and did not manage to take his medications faithfully. Eventually, he died of AIDS,” said study co-lead author, Charles R. Salmen, M.D., M.Phil., the founding director of Organic Health Response.

The intervention was introduced into one set of communities served by the Sena Health Center; other similar neighboring communities in the clinic’s catchment area served as controls. Patients on antiretroviral medications were invited to form microclinic groups. These groups included five to 15 family members, close friends or other members of the patients’ social network, regardless of HIV status. Pre-existing social groups such as churches, soccer teams and money lending clubs were also invited to form microclinic groups and participate. Each microclinic group was assigned a community health worker and a facilitator. All participants received confidential HIV testing and counseling.

“Microclinics are not a traditional support group composed of people confronting a similar challenge, many of whom may not know each other. Instead, microclinics use organic networks to drive positive behavior. And since patients receive support from existing networks, support is sustained,” said study co-author Daniel Zoughbie, M.Sc., D.Phil., chief executive officer of Microclinic International.

The participants attended 10 group-discussion sessions over five months. The sessions educated participants about HIV prevention and treatment, promoted group support through discussions about confidentiality and HIV status disclosure, encouraged group support to assist in taking anti-HIV medications faithfully and making clinic appointments, and encouraged participants to outreach to the community to promote HIV testing and clinic enrollment. At the end of the intervention, participants were invited to take part in voluntary group HIV testing.

“Previously, stigma blocked access to social support because patients didn’t disclose. Microclinics opened up discussion and became the catalyst for destigmatizing HIV. This led to access to support within social networks. Friends and family supported patients in getting to clinic appointments and, in turn, expected appointments to be kept. They supported patients’ taking medications as directed and expected patients to take them. Silence was replaced by active support,” said Hickey.

“UNAIDS has set a goals aiming to have 90 percent of people with HIV in the world successfully treated and retained in care by 2020. The microclinic intervention, which redefines the unit of care from an individual to an individual and his/her social network, is a cost effective, scalable initiative that could help governments meet their targets,” said study co-author, Craig Cohen, M.D., M.P.H., UCSF professor of obstetrics, gynecology and reproductive sciences.

Co-authors include Elvin Geng, M.D., M.P.H., Peter Bacchetti, Ph.D., Cinthia Blat, M.P.H., Robert A. Tessler, M.D., Monica Gandhi, M.D., M.P.H., and Starley Shade, Ph.D., M.S. from UC San Francisco; Betty Njoroge, M.B.Ch.B., M.P.H. and Elisabeth A. Bukusi, M.B.Ch.B., M.Med., M.P.H., Ph.D., P.G.D., from the Kenya Medical Research Institute; Dan Omollo, B.Sc., Brian Mattah, Gor Bernard Ouma, Marcus R. Salmen, M.D., from the Mfangano Island Research Group, Organic Health Response, Kenya; Kathyrn J. Fiorella, M.P.H., from UC Berkeley; and Harold Campbell, Ph.D., from Microclinic International.

Funding for the research was provided by Google Inc via the Tides Foundation, the Craigslist Foundation, the Mulago Foundation, the Rise Up Foundation, Horace W. Goldsmith Foundation, the Segal Family Foundation, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Foundation, and the UCSF School of Medicine’s Dean Research Fellowship.

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Persistence yields progress in AIDS vaccine research at UC Santa Cruz

Phil Berman developing new approach based on old vaccine, advances in HIV immunology.

Veteran vaccine researcher Phil Berman is the Baskin Professor of Biomolecular Engineering at UC Santa Cruz. (Photo by C. Lagattuta, UC Santa Cruz)

By Tim Stephens, UC Santa Cruz

Phil Berman has been working to develop an AIDS vaccine for nearly 30 years, first at the pioneering biotech company Genentech, then as co-founder of VaxGen, and now at UC Santa Cruz, where he is the Baskin Professor of Biomolecular Engineering. Since his arrival at UC Santa Cruz in 2006, Berman has established a major vaccine research effort funded by a series of grants from the National Institutes of Health, including two new grants in 2014 totaling $2.6 million.

The latest results from this effort have Berman sounding optimistic about the prospects for a vaccine that can be effective in protecting against HIV infection. His lab has developed new vaccine candidates that he said are promising enough to consider advancing into clinical trials within the next two years.

Berman has redesigned a vaccine that he invented while at Genentech and led through clinical testing at VaxGen. This earlier vaccine, called AIDSVAX, was used in combination with another experimental vaccine in a large-scale clinical trial in Thailand involving 16,000 people. This trial (known as RV 144) showed that the combined vaccine was safe and 31 percent effective in preventing new HIV infections.

Protective effect

After the results of the trial were released in 2009, Berman and other researchers pored over them to understand the nature of the protective effect. Although the effect was small, RV 144 is still the only clinical trial in which a vaccine has shown any protective effect at all against HIV infection.

“By analyzing the results from RV 144, we started to understand the response to the vaccine, and I developed some new ideas for how to improve it,” Berman said. “By building on an existing vaccine concept, rather than developing a new one from scratch, we can save millions of dollars and years of time getting the new vaccine into the clinic.”

Researchers believe that for an AIDS vaccine to be effective, it must stimulate the immune system to make “broadly neutralizing antibodies” that are effective against multiple strains of the virus. HIV is so highly mutable that replication of the virus in an infected person gives rise to a genetically diverse population of circulating virus, and this variability helps the virus evade detection and neutralization by the immune system.

A neutralizing antibody recognizes a foreign protein (called an antigen), and by binding to it is able to block or neutralize the infectivity of the virus. For example, neutralizing antibodies that target an HIV envelope protein called gp120 can block a crucial part of the infection process in which gp120 binds to a receptor on the surface of T cells. The AIDSVAX vaccine was based on the gp120 envelope protein.

Elite neutralizers

One key to improving the vaccine, Berman said, came from independent lines of investigation pointing to the importance of antibodies that recognize a specific segment of gp120 known as the V1/V2 domain. The RV 144 trial results showed that protection was correlated with antibodies to this domain. Meanwhile, broadly neutralizing antibodies to this domain were isolated from a rare group of people known as “elite neutralizers,” who produce antibodies that potently neutralize multiple strains of the virus.

Studies of these broadly neutralizing antibodies yielded another crucial finding. The part of an antigen that is recognized by an antibody is called an epitope, and it is usually a specific sequence of amino acids in the antigen protein. Scientists studying antibodies from elite neutralizers, however, discovered that many of the most potent neutralizing antibodies actually recognize carbohydrate components called glycans that are attached to the gp120 envelope protein.

“We knew that these broadly neutralizing antibodies existed for many years, but it came as a great surprise that they were directed to carbohydrate epitopes rather than the more common amino acid epitopes,” Berman said. “We found that the vaccine that gave partial protection in the RV 144 trial had very little of the kind of carbohydrate required to bind these antibodies.”

So Berman’s lab set out to produce antigens that would induce a strong antibody response to the glycan-dependent epitopes in the V1/V2 domain. Attaching the right kind of glycans to the protein was just one of the challenges. The envelope protein has dozens of epitopes, and most of the immune response is directed at ones that don’t induce neutralizing antibodies. Compared to these so-called “decoy epitopes,” the glycan-dependent epitopes are only weakly immunogenic. Berman decided to use fragments of gp120 to make protein scaffolds that would present to the immune system only the glycan-dependent epitopes recognized by broadly neutralizing antibodies, while eliminating the other gp120 epitopes.

“The trick is to make the scaffolds fold up into the right three-dimensional shape, as well as incorporating the right glycans,” he said.

Immunogenicity studies

Berman’s lab is now developing cell lines genetically engineered to produce viral proteins with the right structure and glycan epitopes to bind to broadly neutralizing antibodies with high affinity. This strong binding suggests that vaccination with these antigens could stimulate the immune system to produce the broadly neutralizing antibodies. In a paper published last year in the Journal of Biological Chemistry, Berman’s team described the results of immunogenicity studies of these antigens.

“I think we’ve got candidates that should be seriously considered for advancement to clinical testing,” Berman said. “We started with a molecule that has already been tested in humans, and we’ve rebuilt it using envelope proteins and scaffolds with the right carbohydrates.”

Berman’s lab is continuing to generate and screen new cell lines, looking for those that give the most consistent and reproducible production of antigens that perform well in immunogenicity studies. Thanks to NIH funding, he now has the facilities and specialized equipment to conduct rapid screening of cell lines and produce large quantities of proteins for vaccine research.

Berman is also training the researchers and graduate and undergraduate students in his lab in the demanding techniques needed to develop this kind of recombinant vaccine. He noted that plans to repeat the RV 144 trial were stymied by the inability of other labs to reproduce the AIDSVAX vaccine, since VaxGen was no longer in operation. Similarly, he said, efforts to make Ebola antigens for a potential vaccine during the current outbreak in West Africa have been slowed by a shortage of researchers trained in these techniques.

“We’re training people with the skills needed to respond to emerging diseases like Ebola,” Berman said.

Berman’s research is supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute on Drug Abuse (NIDA).

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New clinical model proposed to improve primary care by addressing trauma

Model developed by UCSF clinical researchers and Positive Women’s Network-USA.

By Jeff Sheehy, UC San Francisco

Recognizing that patients’ experiences of childhood and adult trauma are common and have a direct impact on their health, UC San Francisco clinical researchers and Positive Women’s Network-USA have developed and are reporting a new primary care model.

“In our clinic where we treat women with HIV, we are able to deliver lifesaving anti-HIV medications, but we still lose patients far too often. Looking back over the last 10 years, only 16 percent of our patient deaths were due to HIV/AIDS. Most deaths were due to events such as depression, suicide, murder, drug overdoses and lung diseases that are directly related to adult and childhood experiences of trauma. We also realized that trauma is having a devastating impact on the health of a broad spectrum of the U.S. population, regardless of someone’s HIV status. We need a new model of care that addresses this key social determinate of health,” said the paper’s lead author, Edward L. Machtinger, M.D., director of the Women’s HIV Program at UCSF.

The paper presenting the new model will be published in Women’s Health Issues today (May 6).

Trauma can be defined as an event, series of events, or set of circumstances (e.g., childhood and adult physical, sexual and emotional abuse; neglect; loss; community violence; war; and structural violence such as racism) that is experienced by an individual as physically or emotionally harmful or threatening and that has lasting adverse effects.

Research demonstrates that trauma affects large numbers of U.S. men and women, regardless of HIV status. For example, the Centers for Disease Control and Prevention (CDC) estimates that 25 percent of women and 16 percent of men report childhood sexual abuse and that over one-third of women experience stalking, physical violence and/or rape from an intimate partner during their lifetime. The CDC also reports that childhood and adult trauma are strongly linked to the most common causes of adult illness, death and disability in the U.S.

“Understanding the link between trauma and health is an epiphany for clinicians. Many of us have spent years struggling to help our patients improve their health but did not realize that there was a missing ingredient in our model of care. Trauma affects health not only through psychological and behavioral factors, but also biologically, through neuroendocrine and inflammatory changes in response to trauma. By understanding the central role that trauma plays in illness, we can use this new model to re-engineer clinical practice around trauma-informed principles to better serve our patients and save lives,” said Machtinger.

The model represents a fundamental paradigm shift in how primary care is delivered. It is composed of four components – environment, screening, response and foundation.

“For patients who have experienced trauma, the health care environment can seem quite frightening. Some of our current healthcare practices may even trigger patients’ memories of past traumatic events. Because trauma is so common, we need to critically examine how the healthcare environment affects not only patients but also providers and staff. By adopting trauma-informed practices and policies, health care providers and staff promote increased safety, reliability, trust and empathy to create a more healing environment for everyone, said paper co-author Leigh Kimberg, M.D., UCSF professor of medicine at San Francisco Hospital and Trauma Center.

In the trauma-informed primary care model, the health care team routinely inquires about trauma, ideally in the context of an ongoing provider-patient relationship. Patients are educated about the ways that trauma affects health. Screening includes assessment for recent trauma including intimate partner violence, lifetime trauma, and/or the emotional and physical consequences of trauma such as depression, post-traumatic stress disorder (PTSD), substance use and chronic pain.

“Response to trauma disclosure should be empathetic and supportive, validate patients’ experiences, choices and autonomy, get them immediately to safety if needed, and build on their strengths. Providers need to make an effort to understand where a patient is coming from, why they engage in unhealthy behaviors and what they get out of those behaviors,” said paper co-author, Naina Khanna, executive director of Positive Women’s Network-USA.

To help patients heal from past trauma and prevent re-victimization, the researchers say clinics will need to develop onsite trauma specific programs and/or link to community organizations that provide services such as trauma-informed mental health, PTSD reduction and interventions to enhance resilience and coping mechanisms.

“In addition, it is absolutely critical to do lethality assessments of patients at risk of violence and ensure that they get to safe places,” said Khanna.

The foundation of this new primary care model begins with a reexamination of the healthcare setting, starting with the adoption of a core set of values. These values include safety, collaboration, trustworthiness, empowerment and respect for patient choice. In addition, the model includes partnership with community organizations and government agencies, genuine support for providers and staff, and ongoing monitoring and evaluation.

To develop this new paradigm, Machtinger along with other UCSF collaborators partnered with Naina Khanna and the Positive Women’s Network-USA to convene a national working group of leading policy makers, trauma experts and advocates from the government, military, academia, and community organizations. The group, the National Strategy Group to Develop a Model of Trauma-informed Primary Care for Women Living with HIV, identified evidence-based building blocks to create the model presented in the paper

Paper co-authors include Carol Dawson-Rose, R.N., Ph.D., F.A.A.N., professor and Yvette Cuca, Ph.D., M.P.H., specialist from the UCSF School of Nursing.

This work was funded by the Mose J. Firestone Administrative Trust and the California Wellness Foundation.

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UC Irvine study links acute stress response to disaster with prior exposure to traumatic events

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Research links HIV to age-accelerating cellular changes

Study suggests adults infected with virus can develop age-related diseases before peers.

Beth Jamieson, UCLA

By Enrique Rivero, UCLA

People undergoing treatment for HIV-1 have an increased risk for earlier onset of age-related illnesses such as some cancers, renal and kidney disease, frailty, osteoporosis and neurocognitive disease. But is it because of the virus that causes AIDS or the treatment?

To answer that question, researchers at the UCLA AIDS Institute and Center for AIDS Research and the Multicenter AIDS Cohort Study investigated whether the virus induces age-associated epigenetic changes — that is, changes to the DNA that in turn lead to changes in expression of gene levels without changing the inherited genetic code. These changes affect biological processes and can be brought on by environmental factors or by the aging process itself.

In a study published online in the peer-reviewed journal PLOS ONE, the researchers suggest that HIV itself accelerates these aging related changes by more than 14 years.

“While we were surprised by the number of epigenetic changes that were significantly associated with both aging and HIV-infection, we were most surprised that the data suggests HIV-infection can accelerate aging-related epigenetic changes by 13.7 to 14.7 years,” said Beth Jamieson, professor of medicine in the division of hematology/oncology at the David Geffen School of Medicine at UCLA and one of the study’s senior authors. “This number is in line with both anecdotal and published data suggesting that treated HIV-infected adults can develop the diseases of aging mentioned above, approximately a decade earlier than their uninfected peers.”

The researchers examined samples of white blood cells stored by UCLA’s MACS site, which has been collecting biological samples as well as clinical, behavioral and socioeconomic data on men infected with HIV and men at risk for HIV infection since 1983. The scientists selected white blood cell samples from both young (20 to 35 years old) and older (36 to 56) adults who at the time had not started antiretroviral therapy. They divided each group into 12 HIV-infected and 12 age-matched HIV-uninfected samples for a total of 96 samples, and then extracted the DNA from the samples and analyzed it for epigenetic patterns.

They compared epigenetic patterns that are strongly associated with aging to changes that occur during HIV-infection and found significant overlap in the two patterns, and used those overlapping patterns to estimate the biological age of HIV-infected, untreated adults. The researchers found that at the epigenetic level, the adults appeared to be approximately 14 years older than their chronologic age, said Jamieson, who also is director of the UCLA Flow Cytometry Core.

Although the findings demonstrated that HIV infection can accelerate aging-related epigenetics, the researchers could not determine whether antiretroviral therapy restores those patterns to be more age-appropriate or whether the drugs themselves cause additional changes.

Taken together, however, “these data suggest that HIV-1 infection does accelerate some aspects of aging and that general aging, and HIV-1 related aging, work through at least some common mechanisms,” the authors write. “These results are an important first step for finding potential therapeutic approaches to mitigate the effects of both HIV and aging.

The study’s co-authors are Tammy Rickabaugh, Ruth Baxter, Mary Sehl, Janet Sinsheimer, Patricia Hultin, Lance Hultin, Austin Quach, Otoniel Martinez-Maza, Steve Horvath and Eric Vilain, all of UCLA.

The study was supported by a National Institute on Aging grant (1RO1-AG-030327), a UCLA AIDS Institute/CFAR seed grant from the National Institutes of Health (AI-028697) an NIH T032 training grant (5T32GM008243-25) and a National Science Foundation grant (DMS-1264153).

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For most children with HIV, low immune cell count, cells rebound after treatment

Study led by UCLA doctor finds t-cell level returns to normal with time.

Paul Krogstad, UCLA

By Enrique Rivero, UCLA

Most children with HIV who have low levels of a key immune cell eventually recover levels of this cell after they begin treatment, according to a new study conducted by researchers at UCLA and other institutions in the U.S. and Brazil.

The researchers were funded by the National Institutes of Health.

“We were pleased to find that the vast majority of children experience immune system recovery with effective therapy,” said Dr. Paul Krogstad, professor of pediatric infectious diseases and of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, and the study’s first author. “Our study also provided the most detailed information to date about the timing of this recovery in school-age children.”

Krogstad is also a member of the UCLA AIDS Institute and Center for AIDS Research.

CD4+ t cells are a major target of HIV. In about 15 percent of adult patients, the cells fail to rebound after the virus has been suppressed with medication, a scenario that is associated with life-threatening illnesses.

The new study, which was published online in the journal AIDS, was intended to determine to what extent children who were infected with HIV around the time of birth were at risk for this condition and whether this failure carried with it a major risk for serious infection.

The failure of CD4+ t cells to rebound occurs only infrequently in young children with HIV, said Rohan Hazra, a study author and the chief of the maternal and pediatric infectious disease branch at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, which provided much of the funding for the study.

“The comparatively few children whose CD4+ cells failed to rebound did not appear to be at any greater risk for serious infection than children with higher CD4+ counts,” he said.

Hazra added that the findings do not appear to change treatment recommendations for children with HIV: antiretroviral treatment to suppress the virus and periodic follow-up examinations to detect the first signs of any serious infections.

To conduct their analysis, researchers reviewed data from three research networks caring for more than 3,700 children in the U.S., Central and South America, and the Caribbean who were infected with HIV before or during birth. The researchers followed the CD4+ cell counts of 933 children who were at least 5 years old when they started anti-HIV treatment. Healthy CD4+ cell counts range from 500 to 1,200 cells per blood sample. Fewer than 500 cells per sample is considered low, and 200 or fewer per sample is considered very low. After one year of anti-HIV treatment, 86 percent of children in the study achieved CD4+ counts of 500 or more. After two years of anti-HIV treatment, 92 percent surpassed this threshold.

The researchers also reviewed the children’s records for signs of serious illness during the course of their treatment. Known as CDC Category C events, these illnesses are a sign of the seriously weakened immune system in people with AIDS. A total of nine children experienced such events. The occurrence of these events did not differ statistically between those having CD4+ cell counts below 500 at the time of the event (four children) and those with counts above 500 (five children).

The study authors noted that compared to adults with low CD4+ counts at the beginning of treatment, CD4+ counts in children increase to 500 or more with time after treatment has begun. Yet, despite such increases, some children had Category C conditions or other significant illnesses during the first three years of HIV treatment. The researchers wrote that additional studies are needed to understand this higher risk of illness.

Additional funding was provided by several NIH institutes: the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism.

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Building mini-brains to study disorders caused by HIV, meth use

UC San Diego scientist wins $2.5M award to create stem cell-derived models.

By Scott LaFee, UC San Diego

A UC San Diego School of Medicine project involving the creation of miniature models of the human brain – developed with stem cells – to study neurological disorders caused by HIV and methamphetamine use has been named one of five recipients of the 2015 Avant-Garde Award for HIV/AIDS Research from the National Institute on Drug Abuse (NIDA).

The project, headed by Tariq M. Rana, Ph.D., professor of pediatrics, will receive $500,000 per year for five years.

“The human cerebral cortex has evolved strikingly compared to those of other species, and no animal model accurately captures human-specific brain functions,” said Rana. “The creation of mini-brains, or organoids, will permit, for the first time, study of the toxic effects of addiction and HIV on the human brain in a dish. This offers us the exciting opportunity to design patient-specific model systems, which could potentially revolutionize drug discovery and precision medicine for central nervous system disorders.”

The Avant-Garde Awards are granted to scientists who propose high-impact research that could open new avenues for prevention and treatment of HIV/AIDS among drug abusers. The term “avant-garde” is used to describe highly innovative approaches that have the potential to be transformative.

“Despite the success of combined antiretroviral therapies, HIV remains a chronic disease with a host of debilitating side effects that are exacerbated in those suffering from substance use disorders,” said NIDA Director Nora D. Volkow, M.D.  “These scientists have proposed creative approaches that could transform the way we think about HIV/AIDS research, and could lead to the development of exciting new tools and strategies to prevent infections and improve the lives of substance abusers infected with HIV.”

The other 2015 recipients are:

  • Don C. Des Jarlais, Ph.D., Mount Sinai Beth Israel
  • Eli Gilboa, Ph.D., University of Miami School of Medicine
  • Nichole Klatt, Ph.D., University of Washington, Seattle
  • Alan D. Levine, Ph.D., Case Western Reserve University

For more information about the Avant-Garde Award Program and 2015 recipients, visit drugabuse.gov/about-nida.

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Birth control shot linked to moderately increased risk of HIV infection

UC Berkeley findings have potentially broad implications.

By Sarah Yang, UC Berkeley

A large meta-analysis of 12 studies in sub-Saharan Africa found that women who used a type of injectable birth control had a moderately increased risk of becoming infected with HIV.

The contraceptive, depot medroxyprogesterone acetate, is sold under the brand name Depo-Provera, and it is administered as a shot every three months.

The findings, published today in The Lancet Infectious Diseases, included data from 39,500 women. The researchers selected the studies based upon methodological rigor, such as whether they accounted for the use of condoms.

In addition to Depo-Provera, the studies also examined other commonly prescribed forms of hormonal contraception, such as the injectable norethisterone oenanthate (sold as NET-EN), combined oral contraceptives and progestin-only pills. The other birth control methods did not appear to increase HIV infection risk for women in the general population.

“We embarked on this study because of the inconsistency in the scientific literature on this topic,” said study lead author Lauren Ralph, who did this research for her UC Berkeley Ph.D. dissertation in epidemiology. “The results have potentially broad implications because hormonal contraceptives remain popular for women worldwide.”

Approximately 144 million women worldwide use hormonal contraception, and of those about 41 million women use injectable forms of birth control instead of the pill.

The study found that women who used depot medroxyprogesterone acetate had a moderate, 40 percent increased risk of acquiring HIV compared with women using non-hormonal methods and those not practicing birth control. The increased risk was slightly lower, 31 percent, among the studies done in women in the general population.

It remains unclear why the increased risk was seen among those using Depo-Provera but not the other forms of hormonal contraception, the authors said. One possibility may be that birth control with higher levels of progestin, the synthetic form of the natural hormone progesterone, changed the vaginal lining or altered local immunity, increasing the risk for HIV infection, though the researchers emphasized that this study did not examine the physiological effects of the different contraceptive methods and more research on potential underlying biologic mechanisms is needed.

The researchers cautioned that the increased HIV infection risk needs to be considered in the context of the risks associated with not using birth control.

“We do not believe that the findings merit withdrawal of this method of birth control for most women,” said Ralph. “There are significant risks associated with pregnancy and childbirth as well. It can be tricky to ensure a reliable supply of contraceptives in sub-Saharan Africa. Removing Depo-Provera doesn’t mean the women will have immediate access to other methods of birth control that are as effective. Ultimately, decisions around which birth control method to use should be made between a woman and her healthcare provider.”

The researchers noted that the results highlight the need for more studies among high-risk populations.  Among the 12 studies analyzed, only two included sex workers or women with HIV-positive partners.

“The most important next steps for women all over the world are to examine ways to broaden women’s contraceptive options and increase uptake of other safe and effective contraceptive methods, and to step up research on new contraceptive methods, especially those that protect against both HIV and pregnancy,” said senior author Nancy Padian, a UC Berkeley adjunct professor of epidemiology.

Other co-authors of this study are Sandra McCoy, a UC Berkeley assistant adjunct professor of epidemiology, and Karen Shiu, who was a research analyst in Padian’s research group at the time of the study.

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New stem cell technique shows promise in HIV resistance

UC Davis research paves way for human clinical trials using gene therapy.

Joseph Anderson, UC Davis

By Charles Casey, UC Davis

Using modified human stem cells, a team of UC Davis scientists has developed an improved gene therapy strategy that in animal models shows promise as a functional cure for the human immunodeficiency virus (HIV) that causes AIDS.  The achievement, which involves an improved technique to purify populations of HIV-resistant stem cells, opens the door for human clinical trials that were recently approved by the U.S. Food and Drug Administration.

“We have devised a gene therapy strategy to generate an HIV-resistant immune system in patients,” said Joseph Anderson, principal investigator of the study and assistant professor of internal medicine. “We are now poised to evaluate the effectiveness of this therapy in human clinical trials.”

Anderson and his colleagues modified human stem cells with genes that resist HIV infection and then transplanted a near-purified population of these cells into immunodeficient mice. The mice subsequently resisted HIV infection, maintaining signs of a healthy immune system.

The findings are now online in a paper titled “Safety and efficacy of a tCD25 pre-selective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells,” and will be published in the journal Stem Cells.

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A sense for biosensors

UC Irvine’s Weian Zhao has created a device that improves detection of bacterial, viral invaders in blood samples.

The Integrated Comprehensive Droplet Digital Detection system invented by Weian Zhao of UC Irvine converts blood samples directly into billions of very small droplets. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

As a doctoral student at McMaster University in Hamilton, Ontario, Weian Zhao took part in a Canada-wide research effort to develop bioactive paper that would detect, capture and deactivate waterborne and airborne pathogens.

As part of this project, he helped invent gold nanoparticle-coated paper that could detect common pathogens, such as E. coli, but ultimately, the product didn’t meet his exacting standards of diagnostic speed and sensitivity. With a freshly minted Ph.D. in chemistry, Zhao moved on to a joint postdoctoral fellowship at both the Massachusetts Institute of Technology and Harvard, where he dove into stem cell research, his biosensor work seemingly left north of the border.

But the challenge of creating a technology that could rapidly and selectively identify bacterial and viral invaders in blood samples nagged at the young scientist, even as he joined UC Irvine in 2011 as an assistant professor of pharmaceutical sciences with state-of-the-art lab space in the Sue & Bill Gross Stem Cell Research Center.

And then he met Enrico Gratton. In his Laboratory for Fluorescence Dynamics, the UCI biomedical engineer and colleagues have been developing imaging tools for biomedical applications. Among them is a three-dimensional particle counter that tags low-concentration fluorescent particles in large volumes of solution within several minutes, which drew Zhao’s attention. He knew he was back in the biosensor game.

Employing this particle counter, Zhao created a bloodstream infection test that speeds up diagnosis times with unprecedented accuracy – allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

Zhao says that the Integrated Comprehensive Droplet Digital Detection system can, in as little as 90 minutes, detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed. He published his latest results in the November issue of Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” says Zhao, who also holds a faculty appointment in biomedical engineering. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with incipient blood infections.

The Integrated Comprehensive Droplet Digital Detection technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao says that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly identify target bacteria without the purification typically required in conventional assays.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton says. “Importantly, using this technique, we can detect a positive hit from hundreds of millions of measurement samples with very high confidence.”

But invention was only the first step. Zhao wants to commercialize IC 3D. At UCI, faculty researchers with an entrepreneurial bent can work with the Institute for Innovation, an interdisciplinary and campuswide center focused on integrating research, entrepreneurship and technology to create real-world applications that benefit the public and drive the economy. The Office of Technology Alliances, part of the institute, helped Zhao patent-protect the IC 3D technology and establish a spin-off company, Velox Biosystems, to test and manufacture a commercial IC 3D device.

Currently, Zhao is focusing on applying IC 3D to cancer treatments – an extension of the research he’s been advancing since joining UCI.

Zhao has been developing stem cell messengers that selectively migrate to cancer sites to deliver tumor-fighting drugs or probes for contrast-enhanced medical imaging. This could, potentially, enable the identification of cancer micro-metastases at their early stages and increase the effectiveness of chemotherapeutic treatments for metastatic cancer while mitigating the symptoms associated with systemic chemotherapy.

For this work, Zhao was included in the MIT Technology Review’s 2012 list of the world’s top innovators under the age of 35, and this year he earned a prestigious National Institutes of Health Director’s New Innovator Award to further his efforts to create stem cell-based detection methods and treatments for cancer.

He’s also collaborating with Dr. Jason Zell, an assistant professor of medicine and co-leader of the Colon Cancer Disease-Oriented Team at UCI’s Chao Family Comprehensive Cancer Center, to use IC 3D to identify biomarkers in colon cancers. This could enable oncologists to gauge the effectiveness of treatment during the cancer’s early stages more accurately than with current methods, which Zell says are not reliable.

Zhao is now seeking business partners to accelerate Velox Biosystems’ growth and hopes to conduct clinical studies of IC 3D’s utility in patient diagnosis and treatment.

“That’s what’s so important about this project,” he says. “We’ve created a multi-platform tool that has the potential to work with a variety of infections and diseases. I’m very excited about its future.”

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Combining social media, behavioral psychology could lead to more HIV testing

UCLA research suggests a valuable tool in fight against the virus that causes AIDS.

Sean Young, UCLA

By Enrique Rivero, UCLA

Social media such as Twitter and Facebook can be valuable in the fight against HIV in the United States, where research has demonstrated they can prompt high-risk populations to request at-home testing kits for the virus that causes AIDS, suggesting a way to potentially boost testing rates.

But does it lead to actual testing, and can it work outside the United States? A new study from the UCLA AIDS Institute and Center for AIDS Research published online today (Dec. 15) by the peer-reviewed journal Lancet HIV suggests that it can. The study, conducted in Peru among men who have sex with men, found that participants in the intervention arm of a randomized controlled clinical trial were more than twice as likely to be tested for HIV than those who joined a social media group and were provided with traditional HIV prevention services.

The intervention, called Harnessing Online Peer Education (HOPE), combines social media with behavioral psychology to encourage people in high-risk populations to get tested, said Sean Young, assistant professor of family medicine at the David Geffen School of Medicine at UCLA and executive director of the UCLA Center for Digital Behavior.

“This shows that it’s not just social media that got people to test, but the HOPE social media interventions and the psychological ingredients it used for changing behavior,” Young said. “In other words, if you’re a public health organization or worker, don’t just think that throwing something on Facebook or Twitter will solve your problems and change people’s behaviors. Social media may be helpful, but the HOPE intervention was significantly more likely to change HIV testing behavior compared to traditional care through social media.”

Though there have been many experimental HIV testing interventions in international settings, none have used social media technologies, said Young, who is also a member of the UCLA AIDS Institute and Center for AIDS Research, the Center for HIV Identification, Prevention and Treatment Services and the UCLA Center for Addiction and Behavioral Medicine. This study was conducted in greater Lima, which reflects the low- and middle-income countries where low-cost interventions such as HOPE could help stem the spread of AIDS.

Previous research by Young and colleagues demonstrated that the HOPE intervention increased participants’ requests for testing, but was too small to determine the rates of actual testing. “That pilot study was a good enough start showing the potential of using the HOPE intervention to change testing behavior,” he said.

This study builds on the prior research by increasing the number of participants by about five times — 556 participants compared to  112 — and it was designed with a verifiable and observable endpoint allowing the researchers to gauge the rates at which participants followed through with requests for kits and got tested.

The 556 Peruvian men who have sex with men were randomly assigned to join control groups or private intervention on Facebook for 12 weeks, with 278 assigned to each group. The control group received an enhanced standard of care, which included standard offline HIV prevention and testing services offered by local clinics and organizations and participation in Facebook groups that provided study updates and HIV testing information.

The intervention group, by contrast, received the enhanced standard of care and also incorporated the HOPE intervention behavior change model, which utilized peer leaders who sent messages, chats and wall posts and engaged the participants in general friendly conversation. The peer leaders also communicated information about HIV prevention and testing to the participants.

Of the 278 participants in each group, 26 from the intervention group  did not complete the follow-up survey and 32 were lost to follow-up on the control side.  Of the 252 from the intervention group who provided complete data, 43 (17 percent) went on to take an HIV test, compared with 16 (7 percent) of the controls. In the study, seven participants who tested positive were linked to care at a local clinic.

Though this research provides evidence that the HOPE intervention can increase HIV testing in low- and middle-income countries, other settings are different from Peru, so the researchers can’t say for certain if these findings are applicable to other countries.

This study, however, suggests that the HOPE intervention and new technologies can be a low-cost solution for populations at risk for HIV in Peru and other similar low- and middle-income country settings, Young said.

“This could set the stage for important future work on being able to use these methods to treat people who have HIV, which is a tremendous issue in settings like sub-Saharan Africa,” Young added.

Grants from the National Institute of Mental Health (K01 MH090884) and the UCLA AIDS Institute and Center for AIDS Research funded this study.

Study co-authors are William Cumberland, Roch Nianogo, and Thomas Coates of UCLA; Luis Menacho of Universidad Peruana Cayetano Heredia (Peru), and Jerome Galea of Epicentro Gay Men’s Community Center (Lima, Peru).

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