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Gene Editing As A Treatment for HIV

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Taking gene editing from the realm of science fiction to medical reality.

Gene editing, treatment, hiv, zfn, t cells, cd4, lymphocytesThe term  ‘gene editing’ sounds like something out of a science fiction movie. It seems like something that would be used in a plot to create a master race or defeat alien attackers. In reality, scientists are using this technique to treat diseases that currently have no cure. Earlier this month, a group from the University of Pennsylvania published an article in the New England Journal of Medicine in which they used gene editing to treat patients with human immunodeficiency virus (HIV).

HIV is a viral infection that affects immune cells, most notably the CD4+ T cells, which are largely responsible for cell mediated immunity. When CD4+ T cells are depleted, patients’ immune systems become compromised and unable to fight opportunistic infections. A protein called CCR5 (it’s also sometimes called CD195) is a surface receptor that HIV binds to in order to enter and infect host cells. CCR5 is normally a receptor for chemokines and is found on the surface of white blood cells.

Gene editing
The gene editing occurred when scientists isolated CD4+ T cells from HIV patients and treated these cells with an enzyme before injecting the cells back into the patients. The enzyme used was a zinc finger nuclease (ZFN). ZFNs are enzymes which recognize and cleave target sequences in DNA.
A company called Sangamo Biosciences donated the ZFN which cleaves DNA with the CCR5 gene. The cell can repair the break in the DNA strands by one of two methods. Homologous recombination exactly repairs the DNA sequence, but the DNA can just be cut again by the same enzyme. Non-homologous end joining occurs when the breaks are directly joined without using a template for the DNA sequence. This can lead to mutations in the gene, which causes a functional knock out (the protein isn’t expressed or doesn’t work correctly). This technique mirrors a naturally occurring mutation called CCR5 delta 32, which renders people with the mutation resistant to HIV infection.

The study
Twelve HIV positive patients were enrolled in the study. Six patients did not undergo gene editing and served as the control group. Six patients had approximately a billion CD4+ T cells removed and treated, then re-infused. Anti-retroviral therapy was stopped four weeks later to measure viral replication. The authors found that 11-28% of cells treated were genetically modified, and that the decrease in circulating T cells was less in modified cells than in unmodified cells (-1.81 cells/day vs. -7.25 cells/day). However, the number of circulating T cells is not a good estimate of how many T cells are present in the body because most lymphocytes stay in the lymphoid tissue. To address this issue, doctors biopsied the patients and found modified cells in lymph nodes and mucosal tissues. This means it is possible for patients to have more modified cells in their bodies than were present at the time of the initial infusion.

The modified T cells were tracked by a five nucleotide duplication that occurred in 25% of treated cells. The authors did not comment on whether this change was the only modification that occurred after ZFN treatment, or why it was only evident in 1 out of 4 cells. They also did not explain why they did not separate modified cells from unchanged cells to expand the selected mutant cells, which seems like a logical way to increase beneficial effects. There may be technical restrictions to the treatment of the T cells which were not discussed in this paper. Either way, this treatment takes gene editing from the realm of science fiction to medical reality.

References:
Photo: KC Roeyer

Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, & June CH (2014). Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. The New England journal of medicine, 370 (10), 901-10 PMID: 24597865

Gene editing, treatment, hiv, zfn, t cells, cd4, lymphocytes

 

This post was written by Rebekah Morrow:
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