Vanquishing HIV just got that little bit harder. A promising technique to weaken the virus has in some cases made it stronger.
HIV’s ability to evolve resistance to antiretroviral drugs has become legendary. It had been thought that a new precision gene-editing tool called CRISPR would have more success, enabling the viral genome to be “cut” from all infected cells. Now it seems that hope may be in vain – at least for now.
Curing people with HIV has proved impossible so far. Several prominent reports of cures three years ago turned out to provide false hope, after the virus bounced back.
The problem begins with the fact that HIV integrates its genome into the host cell’s DNA. While antiretroviral drugs keep people free of active infection, this viral DNA hides out in parts of the body they can’t reach, ready to revive active infection if the drug treatment is stopped.
Using CRISPR to cut up the HIV genome in all cells – including those where it’s hiding out – is one of several promising strategies to clear the infection.
But it has been hit with a serious setback. Research shows that the use of CRISPR to destroy the virus in white blood cells by messing up its DNA is a double-edged sword.
Chen Liang of McGill University AIDS Center in Montreal, Canada, and his team used CRISPR to cut up the viral DNA that had been incorporated into the host cell. The idea was that when the cell’s natural repair mechanisms patched up the broken genetic sequence it would introduce genetic “scar tissue” that would prevent the viral DNA from functioning.
Sometimes this did, indeed, happen – the gene alterations “killed” the virus. But to the surprise of the researchers, in other cases the scar tissue made the virus stronger – sometimes it was able to replicate faster, for example.
What’s more, because the patched up DNA looks different, the CRISPR cutting system couldn’t recognise and attack it again. HIV had become resistant to the gene-editing technique.
“On the one hand, CRISPR inhibits HIV, but on the other, it helps the virus to escape and survive,” says Liang. “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.”
But all is not yet lost.
“The bright side is that when you know what the problem is, you can come up with the means to overcome it,” says Liang. “Just as HIV is able to escape all antiretroviral drugs, understanding how HIV escapes only helps you discover better drugs or treatments.”
One possibility is to “carpet-bomb” HIV with CRISPR at many sites within its DNA instead of just the one targeted in the experiment. This, says, Liang, would make it much more difficult for the virus to evolve resistance.
Another potential ploy is to attack the virus with CRISPR-like techniques that rely on different DNA repair machinery, making it less likely that the repair process itself would help the virus become resistant to editing.
Another team reporting early success against HIV using CRISPR isn’t discouraged by the setback, echoing the possibility that the “carpet-bombing” solution could be the answer.
“The key could be using multiple viral sites for editing,” says Kamel Khalili of Temple University in Philadelphia, Pennsylvania. “This would reduce any chance for virus escape or the emergence of virus resistant to the initial treatment,” he says.
Earlier this year Khalili’s team showed that CRISPR neutralises HIV in cells that are latently as well as actively infected, suggesting that a cure could one day be possible.
Journal reference: Cell Reports, DOI: 10.1016/j.celrep.2016.03.042
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