Modified enzyme cuts HIV from the DNA of infected human cells
Current HIV/AIDS treatments suppress the virus’s life-cycle without curing the disease. Now, German researchers are pioneering a strategy that might help to eradicate the virus altogether. They have used a specially modified enzyme to cut out HIV-1 from the DNA of infected human cells.
HIV-1 attacks the human immune system’s helper T cells. It is a retrovirus, meaning that its RNA genome inserts itself into the DNA of a host T cell. The insertion requires two enzymes: reverse transcriptase to convert the retrovirus’s RNA into DNA, and integrase to splice transcribed viral DNA into the host’s genome. The provirus, as it is called at this point, then replicates as part of the cell’s DNA, and is inherited when the host cell divides. Enzymes called site-specific recombinases neatly rearrange chunks of DNA in the genome of various organisms. The researchers predicted that a recombinase could be genetically modified to recognise and remove proviral HIV-1 DNA that was integrated into host DNA.
At the end of the HIV-1 DNA sequence there are identical regions of DNA called long-terminal repeats (LTRs). The researchers already knew that a recombinase called Cre recognises a 34-base-pair (bp) symmetric sequence in prokaryotic DNA that has 50 per cent identity with an asymmetric 34-bp sequence in HIV-1 LTRs. But Cre does not recognise the HIV-1 LTRs, so the researchers used a process called molecular evolution to modify the amino-acid sequence of Cre. The result - called Tre - recognises the relevant sequences in HIV-1, resulting in the excision of the provirus from the DNA of experimentally-infected human cervical cancer cells.
’We’re a long way from the clinic,’ said team member Joachim Hauber of the Heinrich-Pette-Institute for Experimental Virology and Immunology in Hamburg, ’but we do at least have a proof-of-principle strategy that could one day form the basis of curative HIV therapies.’
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I Sarkar et al, Science, 2007, 316, 1912 (DOI: 10.1126/science.1141453)