Courtesy / Texas Biomedical Research Institute
San Antonio scientists are once again at the forefront of international scientific research.
Dr. Ruth Ruprecht, director of the Texas Biomed AIDS Research Program and fellow scientists at the Texas Biomedical Research Institute (TBRI), will lead a global team developing a new strategy to combat HIV.
This $23 million project from the National Institute of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID) is the largest program project grant ever received by Texas Biomed, according to TBRI President Robert Gracy.
Dr. Ruprecht and her colleagues have been working on this project for 12 years, but this year’s competitive renewal grant brings in new collaborators and a different strategy.
“We could not have done this anywhere else, the setting in San Antonio could not be more perfect,” Dr. Ruprecht said.
While she led a multi-national HIV research team as professor of medicine at the Harvard School of Medicine and the Dana Farber Cancer Institute, her lab at TBRI – in close proximity to the state of the art Research Imaging Institute (RII) at the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Southwest National Primate Research Center – offered a unique opportunity to expand this research and approach it in a different way.
Growing up in Switzerland, a neutral country in the center of a continent often at war, Dr. Ruprecht heard the stories of the Réduit Suisse. Sometimes referred to as "defense-in-depth," this military strategy relies on a series of defenses to ward off intruders.
Recognizing that the first lines of defense at the border may not hold for long, a second layer of defense would be set in place, and, if necessary, Swiss forces would retreat to a region in the Swiss Alps that would be impenetrable. This region is called the Réduit. It is the core, where everything is protected.
The immune system uses a similar strategy. HIV is the invading army. The immune system stems off invasion at multiple levels, starting at the border. Then, as defenses fall, a second level of immune response kicks in. If that fails, the immune response "retreats" to the Réduit, the last line of defense. Dr. Ruprecht and her colleagues at four institutions in Europe and the United States will work together to develop vaccine targets which will stimulate the human body’s immune system at all of these levels.
The "defense-in-depth" strategy against HIV is broken into three components.
First, Ruprecht's team will establish a better understanding of how the virus penetrates that first-line barrier, the border. These are the mucous membranes. At the same time, they will elucidate how the virus travels through the cells and how the antibodies move. Thomas Hope, Ph.D., professor of Cell & Molecular Biology at Northwestern University’s Feinberg School of Medicine, will use a fluorescent tag to track the virus and the antibodies.
With the state of the art imaging now available at the UTHSCSA’s Research Imaging Institute, the team of Dr. Peter Fox, RII professor and director, and Beth Goins, Ph.D., UTHSCSA professor of radiology, will be able to see how the virus and antibodies travel and interact in their host. Once they understand how this happens, they can develop potential new targets for vaccines.
However, scientists know from previous studies that the first line of defense can break down, so there has to be a second layer of protection.
Previous studies conducted with Dr. Antonio Lanzavecchia, director of the Institute for Research in Biomedicine (IRB) which is part of the Università della Svizzera italiana in Lugano, Switzerland, found surprising results.
The first antibody that HIV comes into contact with is Immunoglobulin A (IgA), produced in the body’s mucosal fluids. Another antibody, called Immunoglobulin G (IgG), is produced in all body fluids. Acting alone, IgA isn’t enough to kill the virus, nor is IgG. But when the scientists combined IgG with IgA, they found 100% protection – HIV did not further invade the cells.
Clearly, the combination of these antibodies has a significant impact upon infection with HIV, even if they don’t act very well on their own.
But how does it work? That will be the task of Dr. Lanzavecchia and Texas Biomed staff scientist Viraj Kulkarni, Ph.D., who will seek to understand how these antibodies interact with the virus and the mucosal cells in the human host. This second layer of defense can be another target for vaccine development.
“But remember the Réduit,” said Dr. Ruprecht.
If the virus evades the first two lines of defense – and it will – it’ll engage in hand-to-hand combat with immune T-cells. These “killer T-cells” can see the cells that have been infected with HIV because the cells express viral proteins. Enter Darrell Irvine, Ph.D., professor of materials science and engineering and biological engineering at the Massachusetts Institute of Technology.
HIV is known to “hide” in the lymph nodes. Indeed, people infected with HIV typically have swollen lymph glands around their neck, which is an early sign of infection.
In developing vaccine candidates that can activate these killer T-cells, Irvine can then put a “tail” onto the vaccine. The tail guides it to the lymph nodes, where HIV often congregates. If the vaccine can find the hidden HIV in the lymph nodes, it can target it specifically, killing the virus.
This work will again require the expertise of UTHSCSA’s Research Imaging Institute, where scientists will use radioactive labels to tag the vaccine. Once tagged, they can follow it using PET and MRI scanning systems to see how the vaccine enters the tissues.
While acting alone, each of these defenses may not be sufficient to stop HIV from ravaging the body. Combined, they may be able to stop infection in its tracks. In being co-located with the Southwest National Primate Research Center, the scientists at Texas Biomed will be able to conduct studies of potential vaccines in a non-human primate model. This critical element of the research will be led by Samir Lakhashe, Ph.D. and Dr. Sandeep Gupta.
And because no research is fully complete without extensive statistical analysis, Sarah Ratcliffe, Ph.D, professor of biostatistics at the University of Pennsylvania, will provide her expertise in the analysis of the data collected.
The AIDS epidemic, now well into its fourth decade, continues to be the worst of the infectious disease outbreaks. In 2015, 36.7 million people worldwide were living with HIV, with 2.1 million new infections each year. In 2014, more than 44,000 people in the U.S. were diagnosed with HIV. Experts estimate that more than 1.2 million people in the U.S. are now living with the virus, many of whom do not know they are infected.
While public health efforts to educate people about the dangers of HIV have been effective in reducing the overall numbers, HIV continues to be a huge burden worldwide. Public health professionals across the globe agree that the best hope for stopping this epidemic lies with a safe and effective vaccine.
Led by San Antonio's own team of experts, the work of this international team will bring humankind closer to that reality.
Top image: Dr. Ruth Ruprecht, M.D., Ph.D., is director of the AIDS Research Program in the Department of Virology and Immunology at the Texas Biomed Research Institute, a world leader in independent biomedical research dedicated to advancing human health across the globe. Photo courtesy of Texas Biomed Research Institute.