Targeting B cells – a new approach to HIV treatment? - Fred Hutchinson Cancer Center

There are currently ~38 million people worldwide living with HIV. If left untreated, HIV infection progresses to acquired immunodeficiency syndrome (AIDS) where patients become extremely vulnerable to other infections and cancers which are usually kept at bay by an intact immune system. This is because HIV infects and kills CD4+ T cells, which are an essential part of a healthy immune system, and whose major function is to help activate other parts of the immune system such as B cells, which secrete antibodies to neutralize microbes, and CD8+ T cells, which kill infected cells and cancer cells.

While progress has been made since the discovery of HIV as the causative agent of AIDS over 40 years ago, there is still no cure. People with HIV can successfully manage the condition by taking daily antiretroviral therapy (ART) medication, which prevents the virus from replicating but does not kill infected T cells. If ART is discontinued, the virus begins to replicate again, and its levels rebound. Latently infected T cells reside in B-cell follicles (BCFs), a lymphoid tissue structure where CD4+ T cells play an important role in B cell development. BCFs exclude CD8+ T cells that can recognize and kill HIV-infected cells, and so they provide a sanctuary for infected CD4+ T cells to persist. But what happens if BCFs are disrupted? Can latently infected T cells be recognized by HIV-specific CD8+ T cells and be cleared from the body? 

In a recent paper in Molecular Therapy, Dr. Christopher Peterson and his team assessed disrupting BCFs as a novel HIV treatment strategy in a non-human primate model of HIV infection. To disrupt BCFs they made use of chimeric antigen receptor (CAR) T cells which are engineered to recognize molecules on the surface of B cells by introducing a CAR against that molecule and are now FDA-approved to treat B-cell lymphomas. Instead of targeting CD19 on lymphoma cells, they engineered CAR T cells to recognize CD20 molecules on follicular B cells. "We were very interested in investigating how well B cell-targeting CAR T cells function in the setting of HIV, which has never been studied despite HIV's association with lymphoma. As we delved deeper, we discovered that CAR T cells possess several mechanisms that could also reduce the HIV reservoir. This realization convinced us the importance of investigating this topic," says Dr. John Bui, co-first author. "This research was really made possible by interfacing with other researchers in the Seattle Cancer Consortium, including Dr. Michael Jensen for his expertise in B cell-targeting CAR T cells and Dr. Joshua Hill for his expertise in adoptive cellular therapies and how they relate to infectious diseases like HIV."

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