Researchers receive NIH grant to help develop gene therapy for HIV

Researchers receive NIH grant to help develop gene therapy for HIV

Researchers at Washington University School of Medicine in St. Louis have received a $6.2 million grant from the National Institutes of Health (NIH) to develop a gene therapy that would alter the immune system's B cells to stimulate them to produce broadly neutralizing antibodies against HIV. Theoretically, such an approach could control or eliminate the infection without the need for ongoing antiretroviral therapy. Shown is the manipulated adenovirus, which is supposed to introduce HIV superantibody genes into B cells.

HIV infections can be controlled with medication, but this therapy must be continued throughout life as there is no strategy to eliminate the virus from the body or control the infection without ongoing treatment.

Aiming to develop such a strategy, researchers at Washington University School of Medicine in St. Louis have received a $6.2 million grant from the National Institutes of Health (NIH) to develop a gene therapy that would jump-start the immune system's B cells so that they produce broadly neutralizing antibodies against HIV. Theoretically, such an approach could control or eliminate the infection without the need for ongoing antiretroviral therapy.

Permanent ways to control or eliminate HIV infection remain elusive, and their development is a major goal of the field. The idea of ​​modifying B cells – which naturally produce antibodies – to ensure that they produce specific antibodies that are generally effective in fighting HIV is an exciting strategy. We have assembled a great team with expertise in HIV, gene therapy and animal models of infection to work toward this goal.”

David T. Curiel, MD, PhD, Distinguished Professor of Radiation Oncology

Curiel's co-principal investigators are Michael R. Farzan, PhD, of Harvard Medical School and Boston Children's Hospital, and Mauricio de Aguiar Martins, PhD, of the University of Florida.

Over the decades since HIV emerged, researchers have found that about 1% of people infected with the virus are capable of producing so-called superantibodies against the virus. Such individuals – so-called elite neutralizers – can produce antibodies against multiple strains of HIV.

“Some people naturally have antibodies that can bind to and destroy or deactivate very different strains of HIV, and we now have the ability to produce these types of antibodies in the laboratory,” said Paul Boucher, a graduate student in Curiel’s lab. "But simply giving other patients these superantibodies is not an ideal solution because these proteins would only remain in the body temporarily. Instead, our approach is to genetically modify the cells responsible for producing antibodies - the B cells of the immune system - so that they can always do it." Produce superantibodies against HIV whenever needed.”

Such engineered B cells could theoretically create a state of permanent vaccination against the virus. Even if such gene therapy does not completely remove HIV from the body, the strategy could allow control of the amount of virus in the body, keeping it at minimal levels and producing a functional cure, according to the researchers.

The strategy is to modify a different type of virus called adenovirus. When used in gene therapy, such viruses are genetically deactivated so that they cannot cause disease. The researchers could then manipulate the adenovirus so that it carries the gene responsible for producing broadly neutralizing antibodies against HIV. In the same viral vector, they could also contain genes responsible for producing the CRISPR/Cas9 gene editing proteins. In this way, the gene therapy delivery vehicle would deliver into the body both the antibody gene that is inserted into the B cell genome and the genes to build the molecular tools to carry out this editing.

Using a three-part targeting strategy, the researchers would design the adenovirus to deliver its genetic payload only to B cells and avoid other cell types. They have developed ways to modify the virus to directly target a protein 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 proteins can only be made when their genes are introduced into B cells. Finally, they developed strategies to modify the adenovirus to stop its natural tendency to accumulate in the liver.

This strategy for modifying B cells is different from another adenoviral gene therapy approach to HIV treatment that is currently in clinical trials led by principal investigator Rachel M. Presti, MD, PhD, a professor of medicine in the Division of Infectious Diseases at Washington University School of Medicine. HIV is difficult to remove from the body because the virus integrates its genome into the DNA of the infected person's T cells. The strategy, currently in clinical trials, focuses on precisely targeting the CRISPR/Cas9 gene editing proteins to remove the virus from the genomes of all infected T cells in a patient. This strategy will be tested in humans for the first time in a Phase 1 clinical trial to determine its safety and preliminary effectiveness at various dosages.

Curiel said engineered B cells are ripe for developing new therapies to treat a variety of diseases. In November, a genetically modified B-cell therapy was administered to a patient for the first time at the University of Minnesota Medical Center. In this case, the therapy was designed to treat mucopolysaccharidosis type 1, a life-threatening disease in which the body lacks an enzyme needed to break down large sugar molecules in cells.

“Gene therapy with engineered B cells is an exciting new area of ​​research,” said Curiel. “We look forward to combining our expertise in adenovirus gene therapy, HIV infection and preclinical disease models to realize our plan to develop an HIV therapy that we hope can provide long-term control of the infection.”

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