Scientists have constructed a custom enzyme that reverses the process by which the human immunodeficiency virus (HIV) inserts its genetic material into host DNA, suggesting that treatment with similar enzymes could potentially rid infected cells of the virus. In tests on cultured human tissue, the mutated enzyme, Tre recombinase, snipped HIV DNA out of chromosomes.
Curing real infections by this or any other technique, however, would require mastering one of HIV's sneakiest tricks—its ability to hide from the immune system by laying dormant for months or years in host cells.
HIV infects the immune system's disease-killing T cells by converting its genome into double stranded DNA and using the enzyme integrase to insert that DNA into a T cell's genome. Researchers have speculated that they could reverse this process with bacterial DNA-cutting enzymes they have adapted for adding and subtracting genes from mice and other multicelled organisms.
To take that step, researchers from the Max Planck Institute for Molecular Cell Biology and Genetics and the University of Hamburg's Heinrich Pette Institute for Experimental Virology and Immunology began with the bacterial enzyme Cre recombinase, which exchanges any two pieces of DNA flanked on either end by a certain pattern of nucleotides (DNA subunits) known as loxP.
HIV does not naturally contain loxP sites, so the team created a hybrid of the two DNA molecules, which they used to select a series of mutated Cre enzymes that were increasingly able to recognize the combined DNA. The final enzyme, Tre, removed all traces of HIV from cultured human cervical cells after about three months, the researchers report online today in Science.
"This is the first demonstration of actual removal of the integrated virus from cells," says Alan Engelman, a molecular virologist at the Dana-Farber Cancer Institute in Boston. The results are promising, he says, but researchers have to make sure the slow-acting Tre enzyme works on real-world strains of HIV and figure out how to safely and precisely administer it in gene form to give it time to snip.
Ideally, Engelman wrote in an editorial accompanying the new report, researchers would like to find a way to send Tre enzymes into the small number of T cells that carry the virus without producing new viral particles, which allows HIV to hide from both antiviral drugs and the immune system.