The search for a cure for AIDS: If it ain’t broke.then break it

The search for a cure for AIDS: If it ain’t broke…then break it

Mar 8th 2014 | From the print edition

GENE therapy usually works by repairing a broken gene or creating a new one where none previously existed. Breaking a working gene to effect a cure is a novel approach. That, though, is what Carl June of the University of Pennsylvania and his colleagues are trying to do. As they explain in the New England Journal of Medicine, by damaging a gene called CCR₅ they hope to treat—and possibly cure—infection with HIV, the virus that causes AIDS.

CCR₅ encodes a protein that sits on the surface membranes of T-lymphocytes, cells which are part of the immune system. The protein’s job is to latch onto signal molecules called chemokines. Unfortunately, it also latches onto strains of HIV, assisting their passage into the lymphocyte, where the virus then reproduces.

A consequence is that those whose CCR₅ genes are broken are immune to infection by these strains. Moreover, an HIV patient called Timothy Brown (pictured) who, in 2007 and 2008, had bone-marrow transplants from a donor with brokenCCR₅ genes, has since been clear of HIV. The lymphocytes that came with the transplant seem to have taken over his immune system and the virus, with nowhere to reproduce, has vanished. Dr June therefore thought that if gene therapy could replace functional CCR₅ genes in T-lymphocytes with broken ones, other people already infected might be cured in a similar way.

He and his colleagues took T-lymphocytes from 12 infected people and tweaked the cells’ CCR₅ genes using enzymes called zinc-finger nucleases. These enzymes recognise and cut particular sequences of the chemical bases of which DNA is composed. Those employed by Dr June were designed to snip CCR₅. Even though a cell attempts to repair DNA so damaged, the fix is often imperfect. The team members were thus able to prepare T-lymphocytes with crocked CCR₅ genes which, they hoped, would be proof against HIV infection. They reinjected these, by the billion, into their volunteers.

The main purpose of this first, small-scale trial was to test the procedure’s safety. It passed. One of the volunteers developed a fever, but that sometimes happens even after ordinary blood transfusions and did not seem abnormal. What really interested everyone, though, was whether the engineered lymphocytes might fend off HIV—and in one case it seems they did.

A month after the transfusion, when the tweaked cells had had a chance to bed down, six of the 12 volunteers stopped taking their antiretroviral drugs, to see what would happen. The engineered cells in these people survived much longer than did other immune cells, suggesting they were resisting infection. And in one of the six volunteers the virus seemed to vanish altogether, as it had done in Mr Brown. Twelve weeks after he stopped taking the drugs, the researchers could find no signs of HIV in his blood.

This individual turned out to be unusual, in that he had inherited a broken CCR₅ gene from one of his parents. That made the nuclease’s task easier, since only one copy of the gene per cell had to be disabled instead of the two copies (one from each parent) that most people have. And, because all the participants are now back on antiretrovirals, whether he would, like Mr Brown, have remained HIV-free indefinitely cannot be known. But his experience gives Dr June and his team hope that they might, possibly, have found a way to clobber a patient’s HIV for good.