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Animal Models

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Gene Editing of Pigs to Control Influenza A Virus Infections

Kwon et al., Emerging Microbes & Infections. 2024.

https://pubmed.ncbi.nlm.nih.gov/39083026/

A reduction in the efficacy of vaccines and antiviral drugs for combating infectious diseases in agricultural animals has been observed. Generating genetically modified livestock species to minimize susceptibility to infectious diseases is of interest as an alternative approach. The researchers developed a homozygous transmembrane serine protease 2 (TMPRSS2) knockout (KO) porcine model to investigate resistance to two influenza A virus (IAV) subtypes, H1N1 and H3N2. TMPRSS2 KO pigs demonstrated diminished nasal cavity viral shedding, lower viral burden, and reduced microscopic lung pathology compared with wild-type (WT) pigs. In vitro culturing of primary bronchial epithelial cells (PBECs) demonstrated delayed viral replication in TMPRSS2 KO pigs compared with WT pigs. This study demonstrates the potential use of genetically modified pigs to mitigate IAV infections in pigs and limit transmission to humans. Supported by ORIP (U42OD011140), NHLBI, NIAID, and NIGMS. 

Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses

Yang et al., Journal of Virology. 2024.

https://pubmed.ncbi.nlm.nih.gov/38323811/

Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.

Thresholds for Post-Rebound SHIV Control after CCR5 Gene-Edited Autologous Hematopoietic Cell Transplantation

Cardozo-Ojeda et al., eLife. 2021.

https://elifesciences.org/articles/57646

Investigators developed a mathematical model to project the minimum threshold of C-C chemokine receptor type 5 (CCR5) gene-edited cells necessary for a functional cure from HIV. This was based on blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted hematopoietic stem and progenitor cells (HSPCs) are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76–94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur. Supported by ORIP (P51OD010425), NCATS and NIAID.