Genetically Modified T-Cells Form a Barrier to HIV Infection

AIDS researchers have used genetically engineered zinc finger nucleases to modify the DNA that produces the T-cell membrane CCR5 receptor resulting in a nonfunctional receptor that prevents infection by the HIV virus.

CCR5, short for chemokine (C-C motif) receptor 5, is a chemokine receptor. The natural chemokines that bind to this receptor are RANTES, MIP-1-alpha and MIP-1-beta. CCR5 is also the name of the gene that codes for the CCR5 receptor. It is located on chromosome 3 on the short (p) arm at position 21. CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.

HIV uses CCR5 or another protein, CXCR4, as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection. Rare individuals who were born with a mutation on their CCR5 gene and therefore do not have a working CCR5 receptor on the surface of their T cells are immune to HIV infection and seemingly are not affected by the non-functional CCR5 protein.
Investigators at the University of Pennsylvania (Philadelphia, USA) employed zinc finger nucleases that had been designed to bind to specific DNA sequences on the CCR5 gene. The enzymes removed a section of the gene, but the repair process generated a mutation that produced a non-functional CCR5 protein.

Results published in the June 29, 2008, online edition of the journal Nature Biotechnology revealed that T-cells that had been removed from HIV infected mice could be treated with the zinc finger nucleases and then returned to the original animals. These mice then showed improvement in the function of their immune systems with much lower numbers of HIV.

"By inducing mutations in the CCR5 gene using zinc finger proteins, we have reduced the expression of CCR5 surface proteins on T cells, which is necessary for the AIDS virus to enter these immune system cells,” explained first author Dr. Elena Perez, assistant professor of pediatrics at the University of Pennsylvania. "This approach stops the AIDS virus from entering the T cells because it now has an introduced error into the CCR5 gene. We followed the mice groups over time and showed that those mice that received the zinc-finger-treated cells showed less viral load than controls and improved CD4 counts.”


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