Researchers identify sustainable source of immunodeficiency virus-resistant immune cells.

Genetic engineering can make immune cells resistant to infection with human or monkey (simian) immunodeficiency virus (HIV and SIV, respectively). Recently, treatment with HIV-resistant immune cells has given encouraging results in patients. Stem cell researchers have now found ways of making large numbers of virus-resistant immune cells from monkeys, allowing future studies on safety and efficacy of immune therapy in a pre-clinical animal model. This encouraging research will help scientists consider alternative approaches to treating HIV, the virus causing AIDS.

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Worldwide, an estimated 37.7 billion people are infected with HIV. Medication is effective in suppressing virus replication and transmission but must be taken life-long on a daily basis, frequently cause side effects, and cannot fully eliminate the virus from the body.

HIV virus predominantly infects and kills certain immune cells called T cells, progressive weakening the patient’s immune system and increasing susceptibility to infections and certain cancers. A potentially effective way of eliminating infected cells and of restoring lost T cells is immunotherapy, where patients’ own T cells are genetically engineered in the lab to make them resistant to HIV infection and subsequently given back to patients. However, only a limited amount of genetically modified T cells can be produced in this way, and the procedures for T-cell isolation, modification, expansion, and re-infusion may compromise their functionality and survival.

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An alternative way of producing T cells in large quantities is making them from induced pluripotent stem cells (iPSCs), which are immature, fast-replicating cells that can be made from patients’ blood or skin cells. iPSCs can be grown in the lab to high numbers, genetically modified, and subsequently be turned into T cells, thus generating large numbers of patient-specific T cells. To test this hypothesis, Igor Slukvin, MD, PhD, and colleagues have set up a pre-clinical model for generating and testing iPSC-derived engineered T cells from monkeys at the Wisconsin National Primate Research Center. Slukvin is a professor of pathology and laboratory medicine at the University of Wisconsin–Madison School of Medicine and Public Health

Using the gene-editing tool, CRISPR/Cas9, researchers deleted the gene coding for a specific protein called CCR5, which is required for viral entry into T cells. Monkey iPSCs with CCR5 deletion were turned into T cells and challenged with simian immunodeficiency virus (SIV), a virus closely related to HIV. Encouragingly, the engineered T cells were protected from infection with SIV, while T cells with intact CCR5 could be readily infected. Follow-up experiments will show if iPSC-derived CCR5 depleted T cells can survive and function in SIV-infected monkeys, with the ultimate goal to control or even eliminate viral infection.

IMAGE CREDIT: Saritha D’Souza, Wisconsin National Primate Research Center, USA

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