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Immune Cells Engineered in Lab to Resist HIV Infection

Tailored gene therapy prevents virus from entering cells (Jan. 22)

Researchers at the Stanford University School of Medicine have found a way to engineer key cells of the immune system so that they remain resistant to infection with human immunodeficiency virus (HIV) — the virus that causes acquired immune deficiency syndrome (AIDS).

The new study — published in Molecular Therapy — describes the use of “molecular scissors” to cut and paste a series of HIV-resistant genes into T cells — specialized immune cells targeted by the AIDS virus. The genome editing was made in a gene that the virus uses to gain entry into cells. By inactivating a receptor gene and inserting additional anti-HIV genes, the researchers blocked the virus from entering the cells, thus preventing it from destroying the immune system, according to principal investigator Matthew Porteus, MD.

“We inactivated one of the receptors that HIV uses to gain entry and added new genes to protect against HIV, so we have multiple layers of protection — what we call stacking,” Porteus said. “We can use this strategy to make cells that are resistant to both major types of HIV.”

He said the new approach, a form of tailored gene therapy, could ultimately replace drug treatment, in which patients have to take multiple medications daily to keep the virus in check and to prevent the potentially fatal infections associated with AIDS. The research was conducted in the laboratory, and clinical trials are needed to determine whether the approach would work as a therapy.

“Providing an infected person with resistant T cells would not cure their viral infection,” said co-author Sara Sawyer, PhD. “However, it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS.”

The new technique hinges on the fact that HIV typically enters T cells by latching onto one of two surface proteins, known as CCR5 and CXCR4. Some of the latest drugs now used in treatment work by interfering with the activity of these receptors. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.

The researchers used a zinc finger nuclease — a protein that can break up pieces of DNA — to zero in on an undamaged section of the CCR5 receptor’s DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said.

Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.

According to Porteus, a potential drawback of the strategy is that while the nuclease is designed to create a break in one spot, it could possibly cause a break elsewhere, leading to cancer or other cell aberrations. He said it’s also possible the cells may not tolerate the genetic change.

Source: Stanford University School of Medicine; January 22, 2013.

Stanford University School of Medicine

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