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ResearchIn-Press PreviewAIDS/HIVHematology Open Access | 10.1172/JCI211637

HIV-resistant CD19/HIV-targeted dual CAR T cells control HIV replication and B cell lymphoma concurrently in humanized mice

Nan Liu,1 David Nardo,1 Vipin Bhardwaj,1 Joshua Glover,1 Divanshu Shukla,1 and James L. Riley1

1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Nardo, D. in: PubMed | Google Scholar

1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Bhardwaj, V. in: PubMed | Google Scholar

1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Glover, J. in: PubMed | Google Scholar

1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Shukla, D. in: PubMed | Google Scholar

1Department of Microbiology and Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Riley, J. in: PubMed | Google Scholar |

Published November 10, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI211637.
Copyright © 2026, Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 10, 2026 - Version history
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Abstract

Infusion of CD19-directed chimeric antigen receptor (CAR) T cells (CARTs) can result in robust CART expansion, long-term CART persistence, and durable remissions in B cell malignancies. We hypothesized that leveraging this expansion and persistence could enable sustained HIV control by engineering IL-18 secreting CD19 CARTs to co-express an HIV-specific CAR and a signaling-deficient C34-CXCR4 HIV fusion inhibitor (C34-CXCR4*), thereby generating HIV-resistant CD19/HIV dual CARTs. These CD19/HIV dual CARTs functioned as well as single CAR expressing CARTs toward a single target indicating no loss of activity occurred by co-expressing the CARs in the same cell. In a humanized mouse model of leukemia infused with CD4 T cells from a person with HIV (PWH), autologous CD19/HIV dual CARTs achieved tumor eradication comparable to that of CD19-only CARTs, demonstrating preserved antitumor efficacy. Notably, a CD19.BBζ–IL-18 CAR combined with a CD4.28ζ-C34-CXCR4* HIV-specific CAR exhibited enhanced T cell expansion and persistence and superior HIV and tumor control. Together, these findings identify CD19/HIV dual CARTs as a promising strategy to maintain a robust population of HIV-specific CARTs to control viral rebound, while simultaneously treating B cell malignancies, advancing CART based approaches toward durable HIV remission.

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