A person with HIV who didn’t take antiretroviral drugs for three months remained free of the virus, thanks to a groundbreaking gene therapy. The success raises the prospect of keeping HIV in check permanently without antiretrovirals.

The gene therapy works by locking the virus out of the CD4 white blood cells it normally infects. Of six people with HIV given the treatment, one cleared the virus completely and another two saw 10-fold drops in circulating virus.

“We’re over the moon to have seen that in this small phase I study,” says Jeff Nichol, executive vice president for research at Sangamo BioSciences, the company in Richmond, California, that is developing the treatment. “Having one virus-free patient and 10-fold reductions in another two is amazing.”

Most importantly, analysis of data from the six patients, and from four others in a separate trial, revealed the secret of the more successful outcomes, paving the way for the therapy to work better in future.


Zinc fingers

To deliver the treatment, doctors remove blood from the patient and isolate CD4 and other white blood cells. Specialised molecular “scissors” called zinc finger proteins enter the cells and sabotage a gene called CCR5, which makes a protein that helps HIV to enter cells. It is unclear what role CCR5 plays normally, although researchers know that cells can survive without it – and will remain uninfected by HIV.

These cells are then returned to the patient in the hope that they will multiply and provide a permanent source of cells immune to HIV, potentially locking out HIV completely. The link between CCR5 and HIV was first suggested in 1996. The concept was first tested inadvertently in Germany in 2006, when a person with leukaemia who was also HIV positive received a bone marrow transplant that happened to come from someone whose blood cells couldn’t make CCR5 proteins. The patient was HIV-free by 2008.

Most people have two working copies of CCR5, one from each parent. The patient who did best in the Sangamo trial already had one defective copy, which is thought to explain why the therapy worked better in him than in the others. Further analysis showed that after the treatment he had twice as many cells in which both copies of the CCR5 gene had been sabotaged than any other trial participant.

The two patients who saw 10-fold reductions in circulating virus also had more doubly sabotaged cells than the three who didn’t respond as well.

Double sabotage

The secret to making the treatment work best, Sangamo says, is therefore to eliminate both genes in as many cells as possible. If only one is sabotaged, cells can still make enough CCR5 protein to allow the virus to invade. In doubly sabotaged, or “bi-allelic” cells, there is no way in.

“The way forward is to get as many bi-allelic cells as possible back into the patient,” says Nichol.

In the light of the findings, Sangamo has plans to try depleting the patient’s native blood system with drugs before returning the altered cells. Depletion causes blood cells to multiply faster than normal to compensate for the shortage, resulting in a more rapid expansion of the numbers of HIV-resistant bi-allelic cells.

Nichol’s colleagues presented the results on Sunday at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.