Gene therapy produces HIV-resistant CD4 T-cells and a first for gene modification of a patients own cells

Gene therapy that interferes with co-receptors on the surface of T-cells can protect these cells from HIV infection, representing a potential first step toward achieving a “functional cure” for AIDS. This was also the first successful use of genetically modified cells from a patients own body being used for treatment. T-cells were filtered from a blood sample, genetically modified, expanded and up 10 to 30 billion genetically modified cells were re-introduced into the patient. The modified cells behaved as regular T-cells. Genetically modifying stem cells could offer longer term and perhaps life long protection.

HIV uses two different surface co-receptors — CCR5 and CXCR4 — to enter CD4 T-cells. If the co-receptors are blocked or disrupted, the virus is unable to enter cells. Two presentations on Monday looked at using gene therapy to create cells that lack these receptor proteins and therefore are protected from infection.

Jay Lalezari from Quest Clinical Research in San Francisco and colleagues used zinc finger nuclease technology developed by Sangamo BioSciences to disable the gene responsible for producing the CCR5 co-receptor on T-cells.

This work draws upon knowledge gained from “elite controllers,” a small proportion of HIV-positive people who have a natural genetic mutation known as CCR5-delta-32. These individuals do not express CCR5 on their T-cells and are able to maintain undetectable or very low viral load without antiretroviral therapy.

Similarly, a man dubbed the “Berlin patient” received two bone marrow transplants to treat leukemia from a donor with the delta-32 mutation. His own immune cells were destroyed by chemotherapy to wipe out the leukemia, and his immune system was reconstituted with cells that lacked CCR5. The man stopped antiretroviral therapy, and three years later researchers are unable to find any trace of HIV.

Given that bone marrow transplants are not feasible on a large scale, investigators are exploring other ways to achieve a similar outcome.

Lalezari’s phase 1 study included six HIV-positive participants on antiretroviral therapy. All were men, most were in their early fifties, and they had been infected for twenty to thirty years. They had undetectable viral load (


Since HIV can use both CCR5 and CXCR4 to enter T-cells, disruption of both co-receptors would be required to fully protect a cell from infection.

Craig Wilen from the University of Pennsylvania and colleagues presented some of the first data on gene therapy to interfere with CXCR4 expression on CD4 cells.

This team also used zinc finger nuclease technology developed by Sangamo. Here too, the nuclease causes a double-strand break in the CXCR4 gene. Mutations introduced during the repair process disable co-receptor expression. Cells with the most common mutation, CXCR4-delta-18, showed little or no surface expression of the co-receptor.

Pre-clinical data were “very promising,” Wilen said. Laboratory cell culture studies showed that the zinc finger procedure did not negatively affect T-cell proliferation. Cell alteration conferred “robust protection.” When exposed to HIV, modified cells with disrupted CXCR4 expression showed a significant survival advantage.

In mice with humanised immune systems, the altered CD4 cells were protected against infection with HIV strains using the CXCR4 co-receptor. A protective effect was evident by 14 days after re-infusion, although the effect waned over time.

Blocking CXCR4 may prove more challenging than blocking CCR5. People with the natural CCR5-delta-32 mutation are generally healthy, with minor immune system variations conferring greater resistance or susceptibility to specific infections. The potential consequences of blocking CXCR4, however, are not fully understood. Wilen noted that the technique under study specifically targets mature CD4 T-cells, which likely would have less effect than targeting CXCR4 in all cell types.

Research to date suggests that it will be necessary to target both CCR5 and CXCR4 in T-cells, Wilen said, and his studies showed that both can be accomplished in the same cell.

Altering mature CD4 T-cells has been shown to confer protection from HIV infection, at least in the short term. But using a similar gene therapy approach on hematopoietic stem cells, which give rise to all types of blood cells including CD4 cells, might confer longer term — and perhaps life-long — protection.

While the apheresis and gene therapy approach is quite expensive initially, researchers are now exploring how the procedure might be scaled up. If cell modification only needs to be repeated infrequently — or better yet, only once ever — it might prove cost effective compared with life-long antiretroviral therapy.

There are 1.1 million Americans living with the Human Immunodeficiency Virus that causes AIDS, and 34 million are infected worldwide, according to the U.S. Centers for Disease Control and Prevention.

Sangamo spokeswoman Liz Wolffe said it’s too early in testing to guess, but it would be “a premier-priced” therapy – in the neighborhood of Dendreon Corp.’s new prostate cancer immune therapy, Provenge – $93,000. Yet AIDS drugs can cost $25,000 a year, so this could still be cost-effective, especially if it’s a cure.

Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naïve Subjects

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