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Robust CAR-T memory formation and function via hematopoietic stem cell delivery
- Source :
- PLoS Pathogens, Vol 17, Iss 4, p e1009404 (2021), PLoS pathogens, vol 17, iss 4, PLoS Pathogens
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.<br />Author summary Engineering T cells with anti-HIV chimeric antigen receptors (CAR) has emerged as a promising strategy to control HIV infection through a genetic vaccination strategy. Here we report a novel CAR-based approach targeting HIV infection using the genetic modification of blood forming hematopoietic stem cells (HSCs). This novel CAR approach uses a modified HIV receptor molecule (the primary HIV receptor CD4) as well as anti-HIV agents to modify HSCs to allow them to develop into cells that are protected from HIV infection and target HIV infected cells for the life of the individual. We found this latest generation of CARs successfully modified and allowed in vivo engraftment that resulted in the development of effective anti-HIV CAR T cells with robust memory formation and viral control. Our study highlights the identification of a next-generation CAR molecule that protected cells from infection, targeted and reduced HIV burdens, and serves as an ideal developmental candidate for further clinical studies.
- Subjects :
- RNA viruses
medicine.medical_treatment
Cellular differentiation
HIV Infections
Pathology and Laboratory Medicine
Lymphocyte Activation
Regenerative Medicine
White Blood Cells
Mice
Spectrum Analysis Techniques
0302 clinical medicine
Immunodeficiency Viruses
Animal Cells
Cellular types
Receptors
Medicine and Health Sciences
Cytotoxic T cell
Biology (General)
0303 health sciences
Receptors, Chimeric Antigen
T Cells
Stem Cells
Immune cells
Hematopoietic stem cell
CD28
Cell Differentiation
Gene Therapy
Flow Cytometry
Infectious Diseases
medicine.anatomical_structure
Spectrophotometry
Medical Microbiology
Viral Pathogens
Antigen
030220 oncology & carcinogenesis
Viruses
Infectious diseases
HIV/AIDS
Cytophotometry
Pathogens
Development of treatments and therapeutic interventions
Stem cell
Infection
Research Article
HIV infections
Biotechnology
Medical conditions
Cell biology
Blood cells
QH301-705.5
T cell
Immunology
Receptors, Antigen, T-Cell
Cytotoxic T cells
Viral diseases
Biology
Research and Analysis Methods
Microbiology
Vaccine Related
03 medical and health sciences
Virology
Retroviruses
Genetics
medicine
Animals
Humans
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
030304 developmental biology
Transplantation
Biology and life sciences
5.2 Cellular and gene therapies
Lentivirus
Organisms
Correction
HIV
Chimeric Antigen
Immunotherapy
RC581-607
Hematopoietic Stem Cells
T-Cell
Stem Cell Research
Chimeric antigen receptor
HIV-1
Cancer research
Immunization
Parasitology
Immunologic diseases. Allergy
Developmental Biology
Cloning
Subjects
Details
- Language :
- English
- ISSN :
- 15537374 and 15537366
- Volume :
- 17
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens
- Accession number :
- edsair.doi.dedup.....4f088fc709ad59baa57abf46431f74e7