HIV destroys its victim’s immune system by infecting T-cells, a type of white blood cell critical for immunity. HIV binds to two different proteins on the T-cell’s surface: CD4 and CCR5.

In the late 1990s, scientists identified a population of individuals seemingly resistant to HIV infection. Despite multiple known exposures, they did not get infected. It turned out that these HIV-resistant individuals had something in common: a mutation in the gene that coded for the CCR5 protein, resulting in a shortened version of the protein appearing on their T-cell’s surface. As a result, HIV simply was not able to efficiently infect their T-cells, so they did not get sick. The mutated CCR5 protein appears to have no negative affect on T-cell function.

Today, Sangamo Therapeutics is applying ZFN genome-editing techniques to disrupt the CCR5 gene of HIV patients’ T-cells. This stops the virus from infecting new cells and restores the immune system. The therapy is currently in Phase 2 clinical trials. These are the first clinical trials of any sort of genome editing.


The idea to knock out the CCR5 protein in the T-cells of HIV-infected patients came from the 2009 reports of the “Berlin Patient”—an HIV patient who received a bone marrow transplant for the treatment of leukemia from an individual with the protective CCR5 mutation. After receiving the transplant, the patient went off his antiviral medications and remained virus free.

The genome editing treatments hope to mimic this success. By isolating T-cells from HIV-infected patients, disabling the gene for the CCR5 protein, and infusing these edited cells back into the patients, doctors will create a population of HIV-resistant cells within the patient. The virus will continue to infect and kill off the unmodified cells, leading to a T-cell population that consists only of HIV-resistant cells. Without a host, the virus will not be able to survive.

For decades, new anti-HIV treatments have been developed, only to have the virus evolve resistance to them. This is because the virus has an unusually high mutation rate—changes to its genetic information happen very frequently due to mistakes that HIV makes when replicating itself. If the virus cannot get into the modified T-cells to replicate, then these mutations will not arise.


Scientists are currently researching multiple ways of editing genomes, but the approach furthest along in clinical development is called ZFN, or “zinc finger nuclease” technology. ZFNs are proteins that have been engineered to recognize a unique DNA sequence and cut the DNA in that location. ZFNs are able to recognize longer DNA sequences than other approaches, such as restriction enzymes, enabling scientists to engineer ZFNs that will cut at a unique location within the human genome.

Once the DNA is cut, cellular enzymes attempt to repair the cut, disrupting the gene in the process. This approach is currently being tested in Phase 2 clinical trials as a potential HIV treatment (see “Curing HIV?”). Researchers are also developing methods to deliver a DNA “repair template” along with the ZFN. In this scenario, the cellular repair enzymes will incorporate the correct version of the gene at the cut site; rather than simply disrupting a dysfunctional gene, they will repair it. ZFN-mediated repair of the hemoglobin gene in sickle cell anemia is currently in preclinical trials.


What do smallpox and HIV have in common? Four percent (4%) to 16% of people of European descent have the CCR5 mutation, protecting them against HIV infection. Interestingly, the smallpox virus—which ravaged Europe from the middle ages until a vaccine was discovered in 18th century—also uses CCR5 to infect cells. It is thought that the CCR5 mutation persisted due to its protection against smallpox.


A restriction enzyme is an enzyme that cuts DNA at a specific nucleotide base (A,T,G, or C) sequence known as restriction sites. Restriction enzymes occur naturally in bacteria where they serve as a defense against invading viruses. Hundreds of different types of restriction enzymes have been isolated from bacteria and are commercially available for use in genetic engineering applications.

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