Michael Brown, PhD, resident member of the Beirne B. Carter Center for Immunology Research (CIC) and Professor of Medicine in the Nephrology Division, received an R01 grant award from the NIH exceeding $3,000,000 for his project “Paired receptor signaling for NK cell virus control and antiviral immunity”. This research will study how two different types of receptors working together can significantly increase the ability of natural killer (NK) cells to increase immune protection against viral infection. NK cells are a specialized type of white blood cell that identify and destroy infected or cancerous cells.
Human immunodeficiency virus (HIV) is a viral infection that destroys the body’s white blood cells. In most patients, this leads to acquired immunodeficiency syndrome (AIDS), where the immune system has been weakened to the point of incompetence. However, a small subset of HIV patients can naturally go their entire lives without developing AIDS and without need of anti-retroviral drug therapy. These ‘elite controllers’ share a distinctive genetic feature. Their NK cells express a specific inhibitory receptor, a kind of molecular sensor, that can bind HLA-B57 (an MHC class I protein) which is found on most cells in people who display extraordinary HIV protection. However, it is unknown how the inhibitory receptor and its HLA-B57 ligand together protect elite controllers from HIV & AIDS.
Brown has long studied mouse NK cells, identifying genes used by NK cells to protect against viral infection. Years ago, his team found that the Ly49G inhibitory receptor and its MHC class I ligand known as H2-Dk in mice was linked with protection against viral infection. Getting to that point was challenging, however, and when he first reported the inhibitory receptor’s protective role, the scientific community was skeptical of his conclusions. “It was a bit of a nightmare,” recalls Brown. His resolve was strengthened by several genetic association studies in humans which reported evidence that both activating and inhibitory NK receptor genes and their MHC class I ligands were linked with protection in HIV patients.
For over a decade, Brown and his team worked to prove in a living organism that the inhibitory receptor was necessary for antiviral immunity. A common method to address this kind of question would be to delete the gene that corresponds to the receptor and observe how the NK cell behavior changes. The genes that encode the different NK receptors are very similar, however, making them difficult to specifically delete. Prior work had shown it was possible to delete multiple NK receptors instead of one, but this would not provide the specificity needed for Brown’s study. So, Brown’s team implemented state-of-the-art CRISPR technology and became the first to remove a single inhibitory receptor gene from the mouse genome. This advance was all that was needed to ultimately prove that the Ly49G inhibitory receptor is required by NK cells to protect against viral infection. Intriguingly, their same study discovered that an activating receptor known as Ly49R works together in a ‘paired fashion’ along with Ly49G to allow NK cells to find and kill virus-infected target cells.
Prior skepticism of the inhibitory receptor’s role meant Brown faced challenges securing external grant funding. In the absence of federal funds, which are critical for staff, materials, and equipment, Brown’s research productivity slowed. Interim support from the Carter Center, School of Medicine, Department of Medicine and Division of Nephrology allowed Brown to continue his work. “I was able to bring this grant in because other folks found ways to keep me here and keep me going, and for that I’m extremely grateful,” he said. This new award will reinvigorate the lab’s program. “I’ll be able to bring in staff and start training graduate students. One of the things I love most is to help young people develop and do what I’ve done in science, and this award will expand my capacity to lead in our training programs.” Extra personnel will accelerate the pace of Brown’s research which seeks to discover how paired receptor systems can enhance NK virus control and antiviral immune protection in both mouse and human studies which can lead to novel strategies to enhance immune protection in chronic viral disease settings.
The Brown Lab is looking to hire at the Research Associate level in the upcoming months. Interested parties should contact Brown via email.