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."
Once infused into animals infected with simian/human immunodeficiency virus (SHIV), CD20-CAR T cells rapidly expanded, trafficked to BCFs, and potently ablated them, depleting the associated follicular T cells. "Our research highlights the remarkable effectiveness of B-cell targeting CAR T cells within lymphoid tissues, causing the reversible ablation of B-cell follicles and T follicular helper cells. With this effect, CAR T cells can expose HIV-infected cells from lymphoid sanctuary sites for targeting by HIV cure strategies." BCF ablation decreased the splenic SHIV reservoir but did not impact other viral reservoir locations, suggesting that CD20 CAR T cells alone are insufficient for total HIV clearance. Although associated with greater lymphodepletion, CD20 CAR T cells were well tolerated in SHIV-infected and healthy animals, supporting the feasibility of this approach in people living with HIV.
In the future, Dr. Peterson and his team hope disruption of BCFs will contribute to a combinatorial HIV reservoir reducing approach. "Our findings support the potential for integrating B-cell depletion strategies into HIV cure approaches. We now have a promising method for exposing HIV-infected cells from lymphoid immune sanctuary sites, opening up avenues to combine this modality with strategies aimed at eliminating infected cells, such as our HIV-targeting CAR T cells." CD20 CAR T cells target an abundant antigen that supports their expansion and killing function, but a major barrier to HIV-specific CAR T cells is a paucity of viral antigen. One potential combination strategy is to co-express the CD20 CAR and HIV-specific CAR in the same T cell to prolong expansion and augment clearance of rare HIV-infected cells.
The spotlighted research was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Hans-Peter Kiem and Keith Jerome contributed to this work.
Bui JK, Starke CE, Poole NH, Rust BJ, Jerome KR, Kiem HP, Peterson CW. (2024) CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence. Molecular Therapy S1525-0016(24)00099-6 doi: 10.1016/j.ymthe.2024.02.030