Using CRISPR to Attack Cytomegalovirus

Here, researchers discuss the use of the gene editing technology CRISPR to combat persistent herpesviruses such as cytomegalovirus (CMV). This is of interest as CMV is implicated in the age-related decline of the immune system, a large part of the frailty of old age. Near all people are infected by CMV by the time they reach old age, and ever more immune cells in the limited number that can be maintained become uselessly specialized to combat CMV, unavailable for other work. These growing efforts are futile, however, as CMV like all herpesviruses cannot be cleared by our immune systems.

What to do about this? Since CMV doesn't actually cause any harm in most people beyond this slow corruption of the immune system, the most straightforward approach is to clear out the unwanted immune cells, a goal that is becoming very plausible in this age of multiple approaches to targeted cell destruction. Clearing out CMV will only be helpful if it is done early enough, however, and the utility of that depends on the pace at which the damage is done. If, like many aspects of aging, damage occurs at a slow pace throughout much of life but accelerates dramatically after age 60 or so, then a therapy to remove CMV may be worth the effort if carried out early enough. If a patient's immune system is already greatly disordered by CMV, then removing the virus from the body won't make a great deal of difference. It won't put things back to the way they were before.

So far, treatment for herpesviruses has been incapable of fully eliminating the virus from its host, meaning the latent infection is lifelong. The virus continues to replicate, which results in flare-ups of disease symptoms in the host. Current treatment for herpesviruses simply mutes the disease symptoms during these flare-ups, but fails to fully eliminate the infection, which will remain latent throughout the life course. Researchers posited that the precision of CRISPR gene editing technology could break the DNA of a herpesvirus, thereby interrupting viral replication. Next, if CRISPR could reach and destroy all existing copies of the virus while also halting replication, then the infection itself could be eliminated.

The researchers tested their theory in three different strains of herpesviruses: Epstein-Barr virus (EBV), Herpes simplex viruses (HSV-1) and (HSV-2), and human cytomegalovirus (HCMV). The results indicate that CRISPR can be used to eliminate replication in all three strains of the virus, but that the technology was so far only successful in actually eradicating EBV. Researchers think this may be because the EBV genome is located in in dividing cells that are easily accessible to CRISPR. Comparatively, the HSV-1 genome targeted by CRISPR is located in closed-off, non-replicating neurons, which makes reaching the genome much more challenging.

"We first need to explore whether these potent anti-viral activities hold up in animal studies, and eventually humans before they may be applied as a future therapy. The first stop is to perform in vivo studies in animal models for these viruses. If these are successful, testing in humans may be the next step. However, there are several hurdles that need to be taken. I think the direct applications to treat EBV and HCMV infections may be challenging, as infected cells can travel to many sites in the body and are hence difficult to reach. For HSV-1, HSV-2, or VZV, delivery may be more straight-forward, as here the viruses reside in limited numbers of neurons at defined areas in the human body, such as the trigeminal ganglia. These sites may be reached by e.g. local administration of neurotropic viral delivery vectors. We envision that delivery of anti-viral CRISPR/Cas9 to latently infected cells may destroy the virus invader, curing the cell in question and preventing future outbreaks. Or, alternatively when we cannot remove the latent genome, pre-load the cell with an anti-viral mechanism that can target newly generated virus once the latent virus become activated. Hence, hopefully we can cure infected individuals, or prevent serious damage upon reactivation of these viruses."



This isn't that exciting as it is still in vitro work. If they can get this working in an animal model that would be more interesting.

Also CRISPR Cas9 could be used to target retrotransposons in the human genome that seem to be repressed, but become activated with age (this type of damage is not on the SENS RF list, although you could argue that it is secondary damage set off by other forms of damage first).

Posted by: Jim at August 9th, 2016 9:22 AM

Actually things may be a little more complicated than this:

"If a patient's immune system is already greatly disordered by CMV, then removing the virus from the body won't make a great deal of difference. It won't put things back to the way they were before."

The thing is that CMV seems to continue to rise in abundance during aging, and immunologists are coming to the view that the dysfunctional T cells that you mention may actually still be doing some of the good things to keep it down. So, if we remove those cells, we'd need to replace them again pretty fast with younger ones, and some people are unsure how readily that would occur. Thus, this kind of effort to get rid of the virus itself may turn out to be a necessary adjunct.

Posted by: Aubrey de Grey at August 24th, 2016 9:27 AM

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