Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo

Wenli Mu; Shallu Tomer; Jeffrey Harding; Nandita Kedia; Valerie Rezek; Ethan Cook; Vaibhavi Patankar; Mayra A. Carrillo; Heather Martin; Hwee L. Ng; Li Wang; Matthew D. Marsden; Scott D. Kitchen; Anjie Zhen

doi:10.1172/JCI185489

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Mu, W. in: JCI | PubMed | Google Scholar |

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Tomer, S. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

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

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Kedia, N. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

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

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Cook, E. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

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

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Carrillo, M. in: JCI | PubMed | Google Scholar |

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Martin, H. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Ng, H. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Wang, L. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Marsden, M. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Kitchen, S. in: JCI | PubMed | Google Scholar

¹Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

²Department of Microbiology & Molecular Genetics, University of Irvine, Irvine, United States of America

Find articles by Zhen, A. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI185489.
Copyright © 2025, Mu 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 February 11, 2025 - Version history

Chimeric Antigen Receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and non-human primates (NHPs) demonstrate that hematopoietic stem cell (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional anti-viral CAR-T cells that reduce viral rebound after ART withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle for sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondria respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells and improved CAR-T control of viral replication. RNAseq analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and the upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound post-ART and reduced HIV reservoir compared to CAR-HSCs alone. These findings suggest that HSCs-based anti-HIV CAR-T combined with rapamycin treatment is a promising approach for treating persistent inflammation and improving immune control of HIV replication.

Version 1 (February 11, 2025): In-Press Preview

Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo

Wenli Mu,¹ Shallu Tomer,¹ Jeffrey Harding,¹ Nandita Kedia,¹ Valerie Rezek,¹ Ethan Cook,¹ Vaibhavi Patankar,¹ Mayra A. Carrillo,¹ Heather Martin,¹ Hwee L. Ng,¹ Li Wang,¹ Matthew D. Marsden,² Scott D. Kitchen,¹ and Anjie Zhen¹

Article tools

Metrics

Go to

Rapamycin Enhances CAR-T Control of HIV Replication and Reservoir Elimination in vivo

Wenli Mu,1 Shallu Tomer,1 Jeffrey Harding,1 Nandita Kedia,1 Valerie Rezek,1 Ethan Cook,1 Vaibhavi Patankar,1 Mayra A. Carrillo,1 Heather Martin,1 Hwee L. Ng,1 Li Wang,1 Matthew D. Marsden,2 Scott D. Kitchen,1 and Anjie Zhen1

Article tools

Metrics

Go to

Sign up for email alerts

Wenli Mu,¹ Shallu Tomer,¹ Jeffrey Harding,¹ Nandita Kedia,¹ Valerie Rezek,¹ Ethan Cook,¹ Vaibhavi Patankar,¹ Mayra A. Carrillo,¹ Heather Martin,¹ Hwee L. Ng,¹ Li Wang,¹ Matthew D. Marsden,² Scott D. Kitchen,¹ and Anjie Zhen¹