Scientists in Germany have constructed a custom enzyme that reverses the process by which HIV inserts its genetic material into a CD4 cell's DNA, suggesting that treatment with similar enzymes could potentially rid infected cells of the virus. According to laboratory study results published in Science, the mutated enzyme—called Tre recombinase—was able to snip HIV DNA out of the chromosomes of cultured human tissue.
While one widespread media report has gone so far as to bill the findings as a "potential cure for HIV," the authors of the study—led by Indrani Sarkar, PhD, of the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden—remain much more reserved. Curing any infection using this technique, they caution, would first 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 CD4 cells by first using the enzyme reverse transcriptase to convert its RNA into double-stranded DNA and then, using the enzyme integrase, to insert the DNA into the 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 multi-celled organisms.
To take that step, Dr. Sarkar's group 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.
According to an editorial accompanying the report, authored by Alan Engelman, PhD, a molecular virologist at the Dana-Farber Institute in Boston, the work of Dr. Sarkar's team is the first demonstration of actual removal of the integrated virus from cells. 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 writes, researchers would like to find a way to send Tre enzymes into the small number of CD4 cells that carry the virus without producing new viral particles, which allows HIV to hide from both antiretroviral drugs and the immune system.
Sources:
Engelman A. AIDS/HIV: a reversal of fortune in HIV-1 integration. Science 316(5833):1855, 2007.
Sarkar I, Hauber I, Hauber J, et al. HIV-1 proviral DNA excision using an evolved recombinase. Science 316(5833):1912, 2007.
