CAR/CXCR5-T cell immunotherapy is safe and potentially efficacious in promoting sustained remission of SIV infection

During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-sp...

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Published in:	PLoS pathogens Vol. 18; no. 2; p. e1009831
Main Authors:	Pampusch, Mary S., Abdelaal, Hadia M., Cartwright, Emily K., Molden, Jhomary S., Davey, Brianna C., Sauve, Jordan D., Sevcik, Emily N., Rendahl, Aaron K., Rakasz, Eva G., Connick, Elizabeth, Berger, Edward A., Skinner, Pamela J.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01.02.2022 Public Library of Science (PLoS)
Subjects:	Animals Antigen receptors, T cell Antigens Antiretroviral therapy Antiviral drugs B-Lymphocytes - immunology Biology and Life Sciences Bone marrow CD4 antigen CD4-Positive T-Lymphocytes - immunology CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell migration Chemokine receptors Chemokines Chimeric antigen receptors Chronic infection Control CXCR5 protein Dendritic cells Drug resistance Follicles Genetic modification Germinal Center - immunology Glycoproteins Health aspects HIV Human immunodeficiency virus Humans Ileum Immune system Immunotherapy Infections Localization Lymph nodes Lymph Nodes - immunology Lymphatic system Lymphocytes Lymphocytes T Lymphoid tissue Macaca mulatta Medicine and Health Sciences Receptors Receptors, Chimeric Antigen - immunology Receptors, Chimeric Antigen - metabolism Receptors, CXCR5 - immunology Receptors, CXCR5 - metabolism Rectum Remission Research and Analysis Methods Ribonucleic acid RNA RNA, Viral Simian Acquired Immunodeficiency Syndrome - immunology Simian Acquired Immunodeficiency Syndrome - therapy Simian immunodeficiency virus Simian Immunodeficiency Virus - immunology Small intestine Spleen T cells Testing Viral Load Viruses United States
ISSN:	1553-7374, 1553-7366, 1553-7374
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Summary:	During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA + cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the ileum, rectum, and lung, and no cells were detected in the bone marrow, liver, or brain. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV-viral RNA + cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 We have read the journal’s policy and the authors of this manuscript have the following competing interests: Pamela Skinner is the co-founder and CSO of MarPam Pharma and has a patent pending US20180371057A1. Mary Pampusch was a former employee of MarPam Pharma. Other authors declare that no competing interests exist.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1009831