Human-immune-system humanized-DRAGA mice are a valuable model to study novel immunotherapies for HIV-1

Pumtang-on, P.; Goodarzi, N.; Davey, B. C.; Sevcik, E. N.; Coleman-Fuller, N.; Vezys, V.; Rao, M.; Pampusch, M. S.; Rendahl, A. K.; Casares, S. A.; Skinner, P. J.

doi:10.1101/2024.12.02.626442

bioRxiv · 10.1101/2024.12.02.626442

Human-immune-system humanized-DRAGA mice are a valuable model to study novel immunotherapies for HIV-1

Pumtang-on, P.·Goodarzi, N.·Davey, B. C.·Sevcik, E. N.·Coleman-Fuller, N.·Vezys, V.·Rao, M.·Pampusch, M. S.·Rendahl, A. K.·Casares, S. A.·Skinner, P. J.

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Abstract

Humanized (h)DRAGA mice are a promising in vivo model for investigating immunotherapies for treating HIV infections. These mice are not only susceptible to HIV infection, but they also develop functional human immune cells, including T cells and B cells as well as follicular-like structures that mimic lymphoid B cell follicles, where HIV-producing cells concentrate during infection in a manner similar to that found in humans. This study evaluated the safety, tissue targeting, and efficacy of follicular-targeting HIV-specific chimeric antigen receptor (CAR)-T cells (CAR/CXCR5-T cells) in HIV-infected hDRAGA mice. Intravenously-infused CAR/CXCR5-T cells persisted in hDRAGA mice for the duration of the study, peaking six days post-infusion. This study indicated that CAR/CXCR5-T cell treatment is safe, with 100% survival rate of treated mice and no noticeable changes in pathology. Six days after infusion, CAR/CXCR5-T cells had accumulated in the follicle-like structures, with many appearing in direct contact with HIV-producing cells. However, CAR/CXCR5-T cell treatment did not appear to reduce viral loads compared to controls, perhaps because many of the engineered CAR/CXCR5-T cells were themselves infected with HIV, with some CAR/CXCR5-T cells showing evidence of HIV virion release. Future studies will investigate whether CAR/CXCR5-T cells engineered for resistance against HIV infection are effective in reducing viral loads. This study supports the approach of using the HIV-infected hDRAGA mouse model to test cellular immunotherapies for HIV, as the model recapitulates many aspects of HIV infection in human lymphoid follicles.

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Pumtang-on, P., Goodarzi, N., Davey, B. C., Sevcik, E. N., Coleman-Fuller, N., Vezys, V., Rao, M., Pampusch, M. S., Rendahl, A. K., Casares, S. A., Skinner, P. J.. 2024-12-05. Human-immune-system humanized-DRAGA mice are a valuable model to study novel immunotherapies for HIV-1. https://doi.org/10.1101/2024.12.02.626442

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