Tag Archives: genome

HIV defies attempt to edit virus out of human cells with CRISPR

Crispr

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.

Story via New Scientist
newscientist

CRISPR cuts

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.

Double-edged sword

“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.

HIV neutralised

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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HIV can “cut & paste” parts in the human genome

genelights

For the first time, researchers have modified HIV virus particles so that they can simultaneously, as it were, ‘cut and paste’ in our genome via biological processes.

Developed by biologists from the Aarhus University, the technology makes it possible to repair genomes in a new way. It also offers new perspectives for treating several viral infections:

“Now we can simultaneously cut out the part of the genome that is broken in sick cells, and patch the gap that arises in the genetic information which we have removed from the genome. The new aspect here is that we can bring the scissors and the patch together in the HIV particles in a fashion that no one else has done before,” says associate professor in genetics Jacob Giehm Mikkelsen from Aarhus University.

HIV has been known for being able to alter the human genome – as a matter of fact, this is the mechanism for every retrovirus out there – that’s just how they work. This mechanism is extremely interesting, and at a very basic level, it works like this: when a retrovirus enters a cell, its genetic information is in the form of RNA, which is different to DNA. The retrovirus uses a special enzyme to make a DNA copy of the RNA genome of the virus; this DNA copy travels to the nucleus of the cell, where it is spliced into the host’s genome, thus ordering it to create new virus particles.

What this research team has done is develop a technique that increases the safety of the cutting process, the so-called “gene editing”:

“In the past, the gene for the scissors has been transferred to the cells, which is dangerous because the cell keeps on producing scissors which can start cutting uncontrollably. But because we make the scissors in the form of a protein, they only cut for a few hours, after which they are broken down. And we ensure that the virus particle also brings along a small piece of genetic material to patch the hole,” says Jacob Giehm Mikkelsen.

According to them, there is no risk of further infection, and it has no negative effects:

“We call this a ‘hit-and-run’ technique because the process is fast and leaves no traces”.

This kind of treatment is called gene therapy – it has been proposed for quite a while, but so far, it has only been trialled with limited success – working around a person’s DNA is extremely dangerous, and cancer is always a potential result. However, if their results are as good as they claim, this might finally overcome that hurdle.

HIV infection is one of the areas where the researchers want to make use of the technique, and here the goal is to stop a specific gene from functioning – something that the protein scissors used here can do.

“By altering relevant cells in the immune system (T cells) we can make them resistant to HIV infection and perhaps even at the same time also equip them with genes that help fight HIV.

“So in this way HIV can in time become a tool in the fight against HIV,” says postdoc and PhD Yujia Cai of the research team.

The scientific paper is available here: Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases

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