Generation of functional human T cell development in NOD/SCID/IL2rγnull humanized mice without using fetal tissue: Application as a model of HIV infection and persistence

Chloé Colas; Olga Volodina; Kathie Béland; Tram N Q Pham; Yuanyi Li; Frédéric Dallaire; Clara Soulard; William Lemieux; Aurélien B L Colamartino; Camille Tremblay-Laganière; Renée Dicaire; Jean Guimond; Suzanne Vobecky; Nancy Poirier; Natasha Patey; Éric A Cohen; Elie Haddad

doi:10.1016/j.stemcr.2023.01.003

Generation of functional human T cell development in NOD/SCID/IL2rγ^null humanized mice without using fetal tissue: Application as a model of HIV infection and persistence

Stem Cell Reports. 2023 Feb 14;18(2):597-612. doi: 10.1016/j.stemcr.2023.01.003. Epub 2023 Feb 2.

Authors

Chloé Colas¹, Olga Volodina², Kathie Béland³, Tram N Q Pham⁴, Yuanyi Li³, Frédéric Dallaire², Clara Soulard¹, William Lemieux¹, Aurélien B L Colamartino¹, Camille Tremblay-Laganière¹, Renée Dicaire³, Jean Guimond⁵, Suzanne Vobecky⁶, Nancy Poirier⁶, Natasha Patey⁷, Éric A Cohen⁸, Elie Haddad⁹

Affiliations

¹ Department of Microbiology and Immunology, Université de Montréal, Montreal, QC H3T 1J4, Canada; CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
² Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada.
³ CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
⁴ Department of Microbiology and Immunology, Université de Montréal, Montreal, QC H3T 1J4, Canada; Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada.
⁵ CSSS Jeanne Mance, Montreal, QC H2X 1K6, Canada.
⁶ Department of Cardiac Surgery, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada.
⁷ CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pathology, CHU Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
⁸ Department of Microbiology and Immunology, Université de Montréal, Montreal, QC H3T 1J4, Canada; Montreal Clinical Research Institute (IRCM), Montreal, QC H2W 1R7, Canada. Electronic address: [email protected].
⁹ Department of Microbiology and Immunology, Université de Montréal, Montreal, QC H3T 1J4, Canada; CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T 1C5, Canada. Electronic address: [email protected].

Abstract

Humanization of mice with functional T cells currently relies on co-implantation of hematopoietic stem cells from fetal liver and autologous fetal thymic tissue (so-called BLT mouse model). Here, we show that NOD/SCID/IL2rγ^null mice humanized with cord blood- derived CD34⁺ cells and implanted with allogeneic pediatric thymic tissues excised during cardiac surgeries (CCST) represent an alternative to BLT mice. CCST mice displayed a strong immune reconstitution, with functional T cells originating from CD34⁺ progenitor cells. They were equally susceptible to mucosal or intraperitoneal HIV infection and had significantly higher HIV-specific T cell responses. Antiretroviral therapy (ART) robustly suppressed viremia and reduced the frequencies of cells carrying integrated HIV DNA. As in BLT mice, we observed a complete viral rebound following ART interruption, suggesting the presence of HIV reservoirs. In conclusion, CCST mice represent a practical alternative to BLT mice, broadening the use of humanized mice for research.

Keywords: HIV; functional T cells; hematopoietic stem cells; humanized mouse model; thymus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Child
Disease Models, Animal
HIV Infections*
Humans
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
T-Lymphocytes
Thymus Gland

Grants and funding

HB2-164064/CIHR/Canada