Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo

Kari-Ann Takano; Anita A L Wong; Rebecca Brown; Kathy Situ; Bernadette Anne Chua; Angel Elma Abu; Truc T Pham; Glania Carel Reyes; Sangeetha Ramachandran; Masakazu Kamata; Melody M H Li; Ting-Ting Wu; Dinesh S Rao; Vaithilingaraja Arumugaswami; Kenneth Dorshkind; Steve Cole; Kouki Morizono

doi:10.1016/j.ymthe.2024.03.002

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo

Mol Ther. 2024 May 1;32(5):1311-1327. doi: 10.1016/j.ymthe.2024.03.002. Epub 2024 Mar 6.

Authors

Kari-Ann Takano¹, Anita A L Wong¹, Rebecca Brown², Kathy Situ¹, Bernadette Anne Chua¹, Angel Elma Abu³, Truc T Pham², Glania Carel Reyes¹, Sangeetha Ramachandran², Masakazu Kamata⁴, Melody M H Li⁵, Ting-Ting Wu⁶, Dinesh S Rao⁷, Vaithilingaraja Arumugaswami⁸, Kenneth Dorshkind⁹, Steve Cole¹⁰, Kouki Morizono¹¹

Affiliations

¹ Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁵ UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Departments of Psychiatry & Biobehavioral Sciences and Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

PMID: 38449314
PMCID: PMC11081870 (available on 2025-05-01)
DOI: 10.1016/j.ymthe.2024.03.002

Abstract

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors, such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

Keywords: B cell receptors; B cells; biodistribution; lentiviral vectors; pseudotyping envelope proteins; targeting; tropism; viral entry; viral receptors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
B-Lymphocytes* / immunology
B-Lymphocytes* / metabolism
Genetic Vectors* / administration & dosage
Genetic Vectors* / genetics
Humans
Lentivirus* / genetics
Mice
Receptors, Antigen, B-Cell* / genetics
Receptors, Antigen, B-Cell* / metabolism
Transduction, Genetic*
Transgenes*
Viral Envelope Proteins* / genetics
Viral Envelope Proteins* / metabolism
Viral Tropism
Virus Internalization

Substances

Receptors, Antigen, B-Cell
Viral Envelope Proteins