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CRISPR can't cut it against HIV

11 April 2016
Appeared in BioNews 846

Scientists testing whether the CRISPR genome-editing technique could effectively kill HIV in infected cells have found that, while the approach works in most cases, it can also cement the virus's presence.

The study appeared just one month after a separate team published research in which CRISPR had been eliminated from cells taken from AIDS patients (see BioNews 845). Researchers from both teams have said that the current study illustrates that there are obstacles in the way of a CRISPR-based therapy for HIV, but these may not be insurmountable.

In the study, scientists used CRISPR to cut out a section of DNA in human cells that is introduced by the HIV when an infection occurs. The genetic code that HIV integrates into the human genome makes cells produce more HIV particles.

In many cases this approach worked – once the viral DNA was removed, the cell automatically patched the section of cut DNA with a different genetic code and the cell no longer produced HIV particles.

But in others the DNA 'patch' actually made the virus stronger, for example by speeding up virus replication. Furthermore, the patched section of DNA was no longer recognisable to the CRISPR system, meaning that any attempt to treat resistant cells for a second time would not work.

'On the one hand, CRISPR inhibits HIV, but on the other, it helps the virus to escape and survive,' senior study author Dr Chen Liang, of McGill University in Montreal, Canada, told New Scientist. 'The surprise is that the resistance mutations are not the products of error-prone viral DNA copying, but rather are created by the cell's own repair machinery.'

However, Dr Liang's team is not the first to observe HIV's resistance to CRISPR. In February, a team from the University of Amsterdam published similar results.

Dr Liang now says that researchers in the field should concentrate on using genome-modifying techniques that could circumvent HIV's resistance. These might include using enzymes other than Cas9 – which is most often used with CRISPR – to cut out viral DNA at different sites, or bombarding cells with CRISPR to cut out viral DNA at several sites instead of just one.

Other researchers in the field are less confident. Professor Bryan Cullen, a virologist at Duke University in the USA, also uses CRISPR as a research tool but was not involved in the current study. He told Nature News that any therapeutic use of CRISPR would require genetically modifying a substantial number of a patients' immune cells. Given the difficulties of such an approach, and the fact that it is becoming easier to manage most HIV infections with cocktails of antiretroviral drugs, Professor Cullen said that he considered CRISPR-based treatments for HIV to be 'pie in the sky'.

Dr Liang's study was published in Cell Reports.
CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape
Cell Reports |  7 April 2016
HIV can develop resistance to CRISPR/Cas9
Eurekalert (press release) |  7 April 2016
HIV defies attempt to edit virus out of human cells with CRISPR
New Scientist |  7 April 2016
HIV overcomes CRISPR gene-editing attack
Nature |  7 April 2016
How HIV Can Escape an Experimental CRISPR Therapy
The Scientist |  7 April 2016
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