Researchers at the Keck School of Medicine of the University of Southern California (USC) have successfully transplanted blood stem cells modified to be resistant to HIV into mice, allowing the animals to control HIV infections. If the approach can be translated to human patients, it would enable the long-term generation of HIV-resistant T cells and other blood cellsin a patient’s body, and the potential for the patient’s own cells to suppress HIV.
The strategy is explained in a new study published online Friday, July 2 in the journal Nature Biotechnology.
“This hybrid gene and stem cell therapy shows that it is possible to create HIV resistant immune cells that can eventually win the battle against HIV in vivo,” said principal investigator Paula Cannon, associate professor of molecular microbiology and immunology at the Keck School of Medicine of USC. “We’ve done it at the scale of a mouse, and the challenge now is to see if this can be done at the scale of a human patient.”
The strategy approach targets a gene called CCR5, which is one of the two gateway molecules that HIV uses to enter human cells. Cannon’s strategy arose from the observation that people with a mutation in a gene called CCR5 are naturally resistant to infection with the most common, CCR5-tropic strains of HIV and do not develop AIDS.
The team used enzymes called zinc finger nucleases—which physically cut DNA—to knock out the CCR5 gene in human hematopoietic blood stem/progenitor cells. They transplanted these modified stem cells into mice, where they develop into mature cells of the human immune system, including the T cells that HIV infects. When they then and later infected the animals with HIV. When they examined the mice at 12 weeks after infection, they found that the mice were able to maintain animals had regained the initial highnormal levels of the human T cells and suppressed HIV to very low levels, unlike control mice that that had received unmodified stem cells.
Cannon’s preliminary data on a specific proteinthe ability of this anti-CCR5 therapy to control HIV replication ? that acts as a cell gateway for HIV led tohas formed the basis of a collaboration between USC, lead institution City of Hope National Medical Center and the biotech company Sangamo BioSciences, Inc. which makes the gene-editing technology. The team received $14 million last year from the California Institute for Regenerative Medicine (CIRM) to develop a this novel therapy further, in the hope that it may offer lifetime immunity to HIV infection. The grant was awarded as part of the Disease Team Research Awards, aimed at speeding the process of bringing stem cell therapies to clinical trials.establishing clinical trials to develop stem cell-based therapies.
“By engineering Hematopoietic stem cells are widely used clinically as they can repopulate the bone marrow and subsequently give rise to all the cell types of the blood, including T cells. The authors suggest that CCR5-deficient stem cells, we may allow a patient to may have the advantage of providing produce longer-term HIV resistant cellsce in all of the cell types that the virus infects, and for long periods of time,” .Cannon said. “If successful, it could one day allow patients to control their HIV without needing to take antiretroviral drugs.”
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Nathalia Holt, Jianbin Wang, Kenneth Kim, Geoffrey Friedman, Xingchao Wang, Vanessa Taupin, Gay M. Crooks, Donald B. Kohn, Philip D. Gregory, Michael C. Holmes, Paula M. Cannon. “Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo.” Nature Biotechnology. doi:10.1038/nbt.1663