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Genetically engineered B cells to produce HIV superantibodies
Currier Laboratory
HIV infection can be controlled with medication, but this treatment must continue throughout the patient’s life because without ongoing treatment, there is no strategy to eliminate the virus from the body or control the infection.
To develop such a strategy, researchers at Washington University School of Medicine in St. Louis received a $6.2 million grant from the National Institutes of Health (NIH) to develop a gene therapy that would modify immune system B cells to stimulate them Generates broadly neutralizing antibodies against HIV. In theory, this approach could control or eliminate the infection without requiring ongoing antiviral treatment.
David T. Curiel, MD, Distinguished Professor of Radiation Oncology, said permanent methods to control or eliminate HIV infection remain elusive and their development is a major goal in the field. The idea of modifying naturally occurring antibody-producing B cells to ensure that they produce broadly and effectively specific antibodies against HIV is an exciting strategy. We have assembled an outstanding team with expertise in HIV, gene therapy and animal models of infection to achieve this goal.
Curiel’s co-principal investigators are Dr. Michael R. Farzan of Harvard Medical School and Boston Children’s Hospital and Dr. Mauricio de Aguiar Martins of the University of Florida.
In the decades since HIV emerged, researchers have learned that about 1 percent of people infected with the virus are able to produce so-called superantibodies that target the virus. These individuals, known as elite neutralizers, can produce antibodies against multiple strains of HIV.
“Some people are born with antibodies that can bind, destroy, or inactivate multiple strains of HIV, and we now have the ability to construct these types of antibodies in the laboratory,” said Paul Boucher, a doctoral student in Curiels’ lab. But simply giving these superantibodies to other patients is not an ideal solution because the proteins will only remain in the body temporarily. Instead, our approach is to genetically modify the immune system’s B cells, which are responsible for producing antibodies, so that they can produce superantibodies against HIV at any time when needed.
In theory, such engineered B cells could create a permanent state of vaccination against the virus. The researchers say that even if this gene therapy cannot completely clear HIV from the body, the strategy can control the amount of virus in the body, keep it at a minimum, and achieve a functional cure.
The strategy involves modifying a different type of virus, called an adenovirus. When used in gene therapy, such viruses are genetically disabled so they cannot cause disease. Researchers can then engineer the adenovirus to carry genes responsible for making broadly neutralizing HIV antibodies. Within the same viral vector, they may also contain the genes responsible for making the CRISPR/Cas9 gene-editing protein. In this way, the gene therapy delivery vector will carry the antibody genes to be edited into the B cell genome and the molecular tools to carry out the edited genes.
Using a three-part targeting strategy, researchers will engineer the adenovirus to deliver its genetic payload only to B cells, avoiding other cell types. They developed ways to modify the virus so that it directly targets proteins expressed on the surface of B cells rather than other cell types. Researchers can further limit targeting by using genetic methods to ensure that the CRISPR/Cas9 protein is only made when its gene is delivered into B cells. Finally, they developed strategies to modify the adenovirus to block its tendency to naturally accumulate in the liver.
This strategy of modifying B cells differs from another adenoviral gene therapy approach to treating HIV that is currently in clinical trials, led by principal investigator Rachel M. Presti, MD, professor of medicine in the Department of Infectious Diseases at Washington University College. HIV is difficult to eliminate from the body because the virus integrates its genome into the DNA of infected individuals’ T cells. The strategy currently undergoing clinical trials focuses on using precise targeting of the CRISPR/Cas9 gene-editing protein to excise the virus from the genome of infected T cells in all patients. This strategy is being tested in a first-in-human Phase 1 clinical trial to determine its safety and preliminary efficacy at different doses.
Engineered B cells are ripe for the development of new treatments for a variety of diseases, Curiel said. In November, the University of Minnesota Medical Center administered genetically engineered B-cell therapy to a patient for the first time. In this case, the therapy is designed to treat mucopolysaccharidosis type 1, a life-threatening disease in which patients lack the enzymes needed to break down large sugar molecules within cells.
Using engineered B cells for gene therapy is an exciting new area of research, Curiel said. We look forward to combining our expertise in adenoviral gene therapy, HIV infection, and preclinical models of disease to advance our plans to develop HIV therapies that we hope will permanently control the infection.
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