Will HIV infection be a thing of the past? (Image: NIAID/National Institutes of Health/Science Photo Library)

Take a hot new method that’s opened up a new era of genetic engineering, apply it to the wonder stem cells that in 2012 won their discoverer a Nobel prize, and you might just have a tool to cure HIV infection.

That’s the hope of researchers led by Yuet Kan of the University of California, San Francisco – and they have proved the basic principle, altering the genome of induced pluripotent stem cells (iPSCs) to give them a rare natural mutation that allows some people to resist HIV.

Kan’s work relies on “genome editing” – snipping out a particular DNA sequence and replacing it with another. It’s much more precise than traditional forms of genetic engineering, in which sequences are added to the genome at random locations.


To alter the stem cells, Kan’s team turned to the CRISPR-Cas9 system, a super-efficient method of genome editing based on an ancient bacterial “immune system”. In bacteria, the system takes fragments of DNA from invading viruses and splices them into the cell’s own DNA, where they act like “wanted” posters, allowing the viruses to be recognised and attacked in future.

Natural resistance

About 1 per cent of people of European descent are resistant to HIV, because they carry two copies of a mutation in the gene for a protein called CCR5. The virus must lock onto this protein before it can invade white blood cells, and the mutations prevent it from doing so.

Using a bone marrow transplant from a naturally HIV-resistant person, Timothy Ray Brown was famously “cured” of HIV infection. Kan’s goal is to achieve the same result without the need to find compatible HIV-resistant bone marrow donors – who are in vanishingly short supply.

It’s fairly easy to make iPSCs from a person’s cells, which then have the potential to grow into any type of cell in the body. So if iPSCs could be given two copies of the protective mutation, it should be possible to make personalised versions of the therapy that cleared HIV from Brown’s body. Kan’s team has now shown that CRISPR-Cas9 can efficiently make the necessary genome edit. As expected, white blood cells grown from these altered stem cells were resistant to HIV upon testing.

“It’s a really fantastic application of the tool,” says Philip Gregory, chief scientific officer with Sangamo BioSciences of Richmond, California. However, he warns that there is a long way to go before it can be turned into a practical therapy.

Transplant hurdle

Kan has not yet grown the iPSCs into the specific type of white blood cells – called CD4+ T cells – that are ravaged by HIV. What he instead plans to do is turn the iPSCs into blood-forming stem cells, which when transplanted into the body would give rise to all of the cell types found in the blood. “One of the problems is converting iPSCs into a type of cell that is transplantable,” says Kan. “It is a big hurdle.”

Regulators will also need to be convinced that cells that have been subjected to extensive genetic manipulation – both to create the iPSCs, and to give them the protective mutation – are safe.

Meanwhile, Sangamo is already testing a therapy that uses an older genome editing technique to disrupt CCR5 in patients’ CD4+ T cells so that HIV is locked out. In an initial clinical trial involving a handful of people with HIV, levels of the virus circulating in the blood decreased – becoming undetectable in one person.

Journal reference: PNAS, DOI: 10.1073/pnas.1407473111