The National Institutes of Health (NIH) has awarded a consortium of Chicago-based institutions, led by Rush University Medical Center, a five-year, $3.75-million grant to establish a Developmental Center for AIDS Research, creating a comprehensive research infrastructure to spur basic science, clinical studies and translational research in the prevention, detection and treatment of HIV infection and AIDS.

The new center is one of only two in the Midwest - the other is in Cleveland, Ohio - and was the only developmental center funded this year. NIH has funded 20 such centers at major academic institutions across the country.

The center in Chicago involves investigators from Rush, the University of Illinois at Chicago (UIC) and Cook County Health and Hospitals System, who will collaborate across disciplines and institutions to advance HIV/AIDS research. Chicago ranks sixth among U.S. cities in the number of HIV cases, with approximately 21,000 known infections and another 5,000 presumed infections.

“With this grant, we have an unparalleled opportunity to make Chicago an epicenter for AIDS research, focusing on translational research that takes investigations from bench to bedside, and out to the community, to make a truly significant impact,” said Alan Landay, PhD, chairman of immunology and microbiology at Rush, director of the new center, and an internationally recognized expert in immunology and HIV pathogenesis.

The NIH funding will be used to create shared “core” facilities that provide expertise and services to participating laboratories at all three institutions.

Rush will head the administrative and developmental cores, with responsibility for strategic planning and operational management. It will oversee scientific communications and funding for important new areas of research and launch a special outreach effort to share advances with the affected community in Chicago.

The University of Illinois at Chicago will direct the basic science and the social and behavioral sciences cores. The basic science core will provide access to, and training in, state-of-the-art technologies for laboratory investigations in virology, molecular biology, immunology and other areas. The social and behavioral sciences core will support research involving social, behavioral and psychosocial issues and facilitate studies and interventions in local, national and international communities.

“Numerous scientists and community activists in our three institutions have been working largely independently to reduce the scourge of HIV/AIDS. This research initiative will provide opportunities for us to share and build upon our varied expertise and perspectives. I fully expect new prevention and treatment strategies to arise from this exciting collaboration,” said Robert Bailey, PhD, professor of epidemiology at the UIC School of Public Health and co-director of the new AIDS research center.

Cook County Health and Hospitals System will direct the clinical core, assisting investigators with clinical and epidemiologic research and facilitating translation of basic science discoveries into the patient care realm. The Ruth M. Rothstein CORE Center for the Prevention, Care and Research of Infectious Diseases, a partnership between Rush and Cook County, sees more than 5,000 HIV-infected individuals each year from diverse communities and has extensive expertise in HIV clinical care and clinical research.

“By including Cook County Health and Hospitals System, the outstanding research team brought together by this grant will be able to address issues that increase HIV-associated morbidity and mortality among the disadvantaged minority populations we serve. That is an extremely important mission for the new center,” said Dr. Audrey French, director of the clinical core and director of research at Cook County’s CORE Center.

The Developmental Center for AIDS Research in Chicago will concentrate its investigations around three themes: HIV and women, with an emphasis on behavior and viral pathogenesis; HIV and aging, including studies of behavioral, cardiovascular, immune system and neurocognitive issues; and HIV and drug abuse, focusing on behavioral questions and neuropharmacology.

Source:
Sharon Butler

Rush University Medical Center

The National Institutes of Health has awarded Albert Einstein College of Medicine of Yeshiva University a four-year, $7.2 million grant to develop a microbicide-releasing vaginal ring to prevent HIV transmission.

“While condoms are excellent at preventing the transmission of HIV, it’s often difficult for women to negotiate their use,” says principal investigator Betsy C. Herold, M.D., professor of pediatrics, of microbiology & immunology, and of obstetrics & gynecology and women’s health at Einstein. “It’s imperative that women have alternative strategies available to protect their own health. Our belief is that an intravaginal ring that delivers a combination of drugs is the best strategy.”

Vaginal rings are soft, plastic, doughnut-shaped devices designed to provide controlled release of drugs to the vagina over extended periods. At present, there are several models available for delivering contraceptives, but none for microbicides.

Dr. Herold and her colleagues will evaluate several anti-HIV microbicides, ultimately aiming for a two-drug combination. “Over the last decade, we’ve learned that when you expose HIV to a single drug, you make it easier to select for resistance,” she says. “So, we are trying to target HIV infection at two different steps very early in its life cycle, which should prevent the establishment of any infection.”

One of the drugs to be evaluated is tenofovir, which blocks reverse transcriptase, an enzyme crucial to HIV reproduction. Tenofovir is used currently as an oral systemic therapy against HIV, but it has also shown promise as a topical microbicide. The team will also test the efficacy of two so-called fusion inhibitors, including maraviroc and PIE12-trimer, which block the virus from entering target immune cells by different mechanisms.

The team will pay particular attention to choosing microbicides that preserve natural vaginal defenses against HIV. In recent years, supposedly safe microbicides were found to make women more susceptible to HIV infection. As Dr. Herold demonstrated in an earlier study, (http://www.einstein.yu.edu/home/news.asp?id=381) these microbicides most likely failed because they disrupted the vagina’s epithelial lining, which provides a protective barrier against infection.

“We want to preserve that protective barrier while adding drugs that will be at the right place at the right time when the virus presents,” says Dr. Herold. “That is why a ring, which can provide sustained delivery of the microbicide over three to four weeks, would be ideal. People wouldn’t have to remember to use it, which is a problem with gels and pills. Also, we don’t know if oral medications will get to the right place - some drugs get into the genital tract well, but some don’t.” The ring could be replaced monthly without a doctor’s supervision.

The microbicides will be incorporated into vaginal ring under development at the University of Utah, Department of Bioengineering, which is collaborating on the study.

“We’ve deliberately chosen to focus on drugs that have already been approved for systemic use or are far along in the regulatory process. This should shorten the time it takes to begin clinical trials. We know that every day that goes by, more people are getting infected with HIV,” says Dr. Herold. The researchers hope to start Phase I clinical testing within the next four years.

The need for a microbicide-releasing vaginal ring is especially urgent in sub-Saharan Africa, where the infection rate among 15 to 49 year-olds exceeds 23 percent in some countries. AIDS is the leading cause of death in sub-Saharan Africa and women account for six out of ten of those living with HIV. “But this is not just a global health problem,” says Dr. Herold. “This is a problem here in the U.S. The rates of HIV in certain regions in this country parallel the rates in many areas of developing world.”

According to the Centers for Disease Control and Prevention, the national infection rate in the United States is 1 percent; in D.C., it is 3 percent, and in the Bronx, 1.7 percent. While men still have higher rates of infection than women in the U.S., AIDS is a common killer for women - ranking third after cancer and heart disease. As of 2007, there were 9,000 women with HIV/AIDS living in the Bronx.

Marla J. Keller, M.D., associate professor of medicine and of obstetrics & gynecology and women’s health at Einstein is a co-investigator on the study. Dr. Keller is a leader in clinical studies on microbicide safety and the impact microbicides have on female genital tract mucosal immunity in HIV-infected and uninfected women. In addition to Dr. Herold, Patrick Kiser, associate professor of bioengineering at the University of Utah, is also a principle investigator on the study. Two biotechnology firms, ImQuest BioSciences, Inc. in Frederick, Maryland, and Particle Sciences, Inc. in Bethlehem, Pennsylvania, are also involved in the study.

Source
Albert Einstein College of Medicine of Yeshiva University

WHAT: New discoveries about anti-HIV antibodies may bring researchers a step closer to creating an effective HIV vaccine, according to a new paper co-authored by scientists at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Scientists know that an HIV-neutralizing antibody called b12 binds to gp120, an HIV surface protein, at one of the few areas of the virus that does not mutate: the site where gp120 initially attaches to human immune cells (http://www3.niaid.nih.gov/news/newsreleases/2007/b12antibody.htm). It was thought that exposing the human immune system to this site on gp120 would generate antibodies that, like b12, can neutralize HIV. Studies have found that for unknown reasons, however, the vast majority of antibodies that recognize this site do not block the virus from infecting cells. Now a new study solves this puzzle, suggesting that antibodies must home in precisely on the site of initial gp120 attachment to successfully neutralize HIV.

The gp120 protein usually appears on the surface of HIV and on infected cells in inactive forms of viral debris or non-functional viral spikes. Only rarely do gp120 molecules appear on the surface of the virus in a functional viral spike, which contains a cluster of three gp120 molecules, known as a trimer, in specific alignment. HIV uses this functional viral spike to bind to immune cells and infect them.

The new study shows that most antibodies able to bind to non-functional forms of gp120 cannot bind to gp120 in the functional viral spike and therefore cannot neutralize HIV. Further, the study demonstrates that the reason most anti-gp120 antibodies similar to b12 cannot bind to the functional viral spike is because of the way these antibodies attach to gp120. A close examination of two such antibodies illustrated that their binding positions on gp120 cause a key portion of the protein either to swing in or flare out in positions incompatible with the trimer structure. In contrast, the position of b12 antibody binding allows gp120 to neatly form its normal trimeric structure.

The scientists conclude that generating HIV neutralizing antibodies will require teaching the immune system to make antibodies that precisely target the site of vulnerability on gp120 as it appears in the functional viral spike rather than targeting the plentiful forms of viral debris such as single gp120 molecules.

ARTICLE: L Chen et al. Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science DOI 10.1126/science.1175868 (2009).

WHO: Peter D. Kwong, Ph.D., and John R. Mascola, M.D., chiefs of the Structural Biology Section and BSL-3 Core, respectively, in the NIAID Vaccine Research Center, as well as Gary J. Nabel, M.D., Ph.D., director of the Vaccine Research Center.

Source: Laura Sivitz

NIH/National Institute of Allergy and Infectious Diseases