Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals

Jeffrey M Jacobson; Julie K Jadlowsky; Simon F Lacey; Joseph A Fraietta; Gabriela Plesa; Hideto Chono; Dong H Lee; Irina Kulikovskaya; Chelsie Bartoszek; Fang Chen; Lifeng Tian; Alexander Dimitri; Bruce L Levine; Elizabeth A Veloso; Wei-Ting Hwang; Carl H June

doi:10.1016/j.ymthe.2020.11.007

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Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals

Journal article

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Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals

Jeffrey M Jacobson, Julie K Jadlowsky, Simon F Lacey, Joseph A Fraietta, Gabriela Plesa, Hideto Chono, Dong H Lee, Irina Kulikovskaya, Chelsie Bartoszek, Fang Chen, …

Molecular therapy, v 29(2), pp 626-635

03 Feb 2021

DOI: https://doi.org/10.1016/j.ymthe.2020.11.007

PMID: 33186691

Featured in Collection : UN Sustainable Development Goals @ Drexel

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Abstract

CD4 Lymphocyte Count

CD4-Positive T-Lymphocytes - immunology

CD4-Positive T-Lymphocytes - metabolism

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Endoribonucleases - genetics

Endoribonucleases - metabolism

Escherichia coli Proteins - genetics

Escherichia coli Proteins - metabolism

Genetic Therapy

HIV Infections - immunology

HIV Infections - metabolism

HIV Infections - therapy

HIV Infections - virology

HIV-1 - physiology

tat Gene Products, Human Immunodeficiency Virus - metabolism

Viral Load

Virus Replication

MazF is an Escherichia coli-derived endoribonuclease that selectively cleaves ACA sequences of mRNA prevalent in HIV. We administered a single infusion of autologous CD4 T lymphocytes modified to express a Tat-dependent MazF transgene to 10 HIV-infected individuals (six remaining on antiretroviral therapy [ART]; four undergoing treatment interruption post-infusion) in order to provide a population of HIV-resistant immune cells. In participants who remained on ART, increases in CD4 and CD8 T cell counts of ~200 cells/mm each occurred within 2 weeks of infusion and persisted for at least 6 months. Modified cells were detectable for several months in the blood and trafficked to gastrointestinal lymph tissue. HIV-1 Tat introduced ex vivo to the modified CD4 T cells induced MazF expression in both pre- and post-infusion samples, and MazF expression was detected in vivo post-viral-rebound during ATI. One participant experienced mild cytokine release syndrome. In sum, this study of a single infusion of MazF-modified CD4 T lymphocytes demonstrated safety of these cells, distribution to lymph tissue and maintenance of Tat-inducible MazF endoribonuclease activity, as well as sustained elevation of blood CD4 and CD8 T cell counts. Future studies to assess effects on viremia and latent proviral reservoir are warranted.

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6 citations in Web of Science

5 citations in Scopus

Details

Title: Autologous CD4 T Lymphocytes Modified with a Tat-Dependent, Virus-Specific Endoribonuclease Gene in HIV-Infected Individuals
Creators: Jeffrey M Jacobson - Case Western Reserve University
Julie K Jadlowsky - University of Pennsylvania
Simon F Lacey - University of Pennsylvania
Joseph A Fraietta - University of Pennsylvania
Gabriela Plesa - University of Pennsylvania
Hideto Chono - Takara Bio Inc., Shiga, Japan
Dong H Lee - Drexel University
Irina Kulikovskaya - University of Pennsylvania
Chelsie Bartoszek - University of Pennsylvania
Fang Chen - University of Pennsylvania
Lifeng Tian - University of Pennsylvania
Alexander Dimitri - University of Pennsylvania
Bruce L Levine - University of Pennsylvania
Elizabeth A Veloso - University of Pennsylvania
Wei-Ting Hwang - University of Pennsylvania
Carl H June - University of Pennsylvania
Publication Details: Molecular therapy, v 29(2), pp 626-635
Publisher: Elsevier
Grant note: P30 CA016520 / NCI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Biology
Web of Science ID: WOS:000632042300023
Scopus ID: 2-s2.0-85096865399
Other Identifier: 991019168370704721

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Web of Science research areas: Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental