iPSC-Derived CCR5 Depleted T Cells Show Protection Against SIV

Wisconsin researchers report a more robust method of producing immunodeficiency virus-resistant immune cells in monkeys, findings that could potentially lead to improved treatment for human immunodeficiency virus (HIV).

HIV predominantly infects and kills immune cells called T cells, progressively weakening the patient’s immune system and increasing susceptibility to infections and certain cancers. An estimated 37.7 million people are infected with the virus globally. 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. 

A potentially effective way of eliminating infected cells and of restoring lost T cells is immunotherapy, where a patient’s own T cells are genetically engineered in a lab to make them resistant to HIV infection and then reintroduced to the patient. However, only a limited amount of genetically modified T cells can be produced in this way, and the complicated procedures and logistics for T-cell isolation, modification, expansion, and re-infusion can compromise the cells’ functionality and survival.

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 turned into T cells, thus generating large numbers of patient-specific T cells.

To test this the viability of this method, Igor Slukvin, MD, PhD, and colleagues at University of Wisconsin–Madison School of Medicine and Public Health set up a pre-clinical model for generating and testing iPSC-derived engineered T cells from monkeys at the Wisconsin National Primate Research Center. Using CRISPR/Cas9, the team 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 examine 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.

The findings were published recently in Stem Cell Reports.