Multidisciplinary approach to remove all traces of HIV from the body while treating existing substance use disorders / addictions
University of Maryland School of Medicine (UMSOM) Professor of Diagnostic Radiology and Nuclear Medicine, Linda Chang, MD, MS, received the 2021 Avant Garde Award (DP1) from the National Institute on Drug Abuse (NIDA) for research into HIV / AIDS and substance use disorders – a pioneer award from the National Institutes of Health (NIH). This prestigious award supports researchers with exceptional creativity who propose highly effective research that has the potential to change the field. Your proposed project will involve a team of experts in brain imaging, infectious diseases, addiction, animal research and gene editing technology, with the goal of eradicating essentially all traces of HIV from the body and treating common substance use disorders. Avant Garde award winners are expected to earn more than $ 5 million over five years in 2021.
“I am very pleased and very happy to have received this award,” says Dr. Chang, who has a second job in the Department of Neurology at UMSOM. “This project takes my work in a new direction. I believe that my track record of working across disciplines with various researchers to initiate new areas of research and achieve good results, along with the excellent staff and resources at UMB, has given the application reviewers confidence that my team and I can make significant progress this new project. “
According to the Centers for Disease Control and Prevention, around 38 million people worldwide live with HIV. Although antiretroviral therapies can treat HIV to undetectable virus levels and lead to a long, healthy lifespan, these drugs must be taken for life to prevent resurgence as HIV can hide from these drugs by making copies of itself Integrated genome of a person. Once the drugs are stopped, the virus can reappear.
From start to finish, it’s Dr. Chang’s plan to remove HIV from the genome, even in hard-to-reach places like the brain, bring more antiretroviral therapies to the brain, and stimulate the brain’s reward system to reduce drug cravings. The work begins on mice before it can be tested on humans.
Dr. Chang plans to use CRISPR gene-editing technology to cut copies of the HIV genes hidden in the genome of mice so that antiretroviral drugs can eradicate them.
However, getting CRISPR therapy into the brain can be difficult because of the blood-brain barrier that protects the brain from infectious bacteria and foreign substances. The blood-brain barrier also prevents antiretroviral drugs from reaching high levels in the brain and central nervous system to effectively destroy HIV.
To detect HIV in the brain, Dr. Chang and her team temporarily interrupt the blood-brain barrier to allow more antiretroviral drugs or the CRISPR compounds to cross the blood-brain barrier – the MRI-guided focused ultrasound system. This technique uses the MRI scan to guide 2,000 pinpoint beams of high-energy sound waves along with microscopic bubbles to non-invasively and temporarily open an area of the brain with the aim of eliminating the virus reservoirs hidden in the brain’s immune cells.
About half of people with HIV use substances such as drugs or alcohol, or have substance abuse disorders. Even tobacco or cannabis use among people with HIV is 2-3 times higher than that of the general population. Together with Victor Frenkel, PhD, Associate Professor in the Department of Radiology and Director of Translational Focused Ultrasound, and Donna Calu, PhD., Assistant Professor in the Department of Anatomy and Neurobiology, Dr. Chang uses low-energy MR-guided focused ultrasound to suppress brain activity in the brain’s reward center, the nucleus accumbens. They hope this approach will suppress drug cravings in people living with HIV who have drug use disorders.
The various components of this project will first be tested in mouse or rat models before moving on to clinical studies. Because HIV does not normally infect mice, researchers use “humanized” mice with weak immune systems, which are replaced with human blood stem cells, which become human immune cells that can be infected with HIV. Although these humanized mice produce many T cells – a major cell responsible for HIV infection – they do not produce the immune cells that HIV uses to hide in the brain, known as microglia. Recently, Dr. Chang’s associate Howard E. Gendelman, MD, Margaret R. Larson, professor of internal medicine and infectious diseases at the University of Nebraska Medical Center, and his lab developed a modified humanized mouse that has an additional human gene that enables humans to produce blood stem cells to form microglia now.
“These new mice mean these experiments can be done in a fraction of the time and cost, and without the other hurdles associated with using non-human primates, which are the only other animals that infect a specific strain of HIV can. ”says employee Alonso Heredia, PhD, associate professor for medicine and scientist at the Institute for Human Virology at UMSOM.
He adds, “There have been many attempts to eradicate HIV in the body and are believed to have been unsuccessful, in part because we cannot reach the HIV reservoirs in the brain. If that works, we will be much closer to a practical cure for HIV. ”Dr. Heredia is working with Dr. Chang, using HIV-infected humanized mice that he developed for his other ongoing projects.
For the addiction studies, the team led by Dr. Chang leveraged the expertise and rodent addiction models developed by Mary Kay Lobo, PhD, Professor of Anatomy and Neurobiology, and Dr. Calu have been developed and optimized. The mice self-administer fentanyl, a powerful synthetic opioid.
Dr. Frenkel and Dheeraj Gandhi, MBBS, Professor of Diagnostic Radiology and Nuclear Medicine and Clinical Director of the Center for Metabolic Imaging and Therapeutics at UMSOM, are the team’s MRI-guided experts in focused ultrasound and clinical research.
“My heartfelt congratulations to Dr. Chang and her colleagues and employees. If something is called ‘cutting edge’, then this work certainly deserves that praise. We wish this group every success, ”said Robert C. Gallo, MD, The Homer & Martha Gudelsky Distinguished Professor in Medicine, Co-Founder and Director, Institute of Human Virology (IHV), University of Maryland School of Medicine, a Global Virus Network ( GVN) Center of Excellence and GVN co-founder and international scientific advisor.
Dr. Chang is an expert on using brain imaging to study how HIV or drug use affects the brain in adults and in adolescence, and how exposure to drugs in the womb affects child development. She has also conducted clinical studies on the treatment of HIV-associated cognitive and substance use disorders.
Dr. Chang came to UMSOM in 2017 through the Dean’s Special Trans-Disciplinary Recruitment Award Program (STRAP). The STRAP initiative was part of UMSOM’s multi-year ACCEL-Med (Accelerating Innovation and Discovery in Medicine) research strategy to increase the quality and reputation of clinical and basic science research and make UMSOM other high-level medical research schools.
“DR. Chang’s arrival at UMSOM spurred the very kind of collaboration we wanted through our recruiting program to accelerate discoveries, treatments, and cures for the world’s most pressing diseases,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President of Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Distinguished Professor and Dean, UMSOM. “I look forward to following your team’s progress on this ambitious project in the hope that we One day we can eradicate HIV. “
Dr. Chang served on the National Advisory Council on Drug Abuse for NIDA and is currently a member of the NIH Council of Councils.
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