Potential MIT virus breakthrough?

[imiyakawa]

MIT Lincoln Laboratory researchers develop a technique to cure a broad range of viruses
Viral pathogens pose serious health threats worldwide. For clinical viruses such as HIV or hepatitis, emerging viruses such as avian or swine influenza, and highly lethal viruses such as Ebola or smallpox that might be used in bioterrorist attacks, relatively few therapeutics or prophylactics (preventatives) exist. Most therapeutics that do exist are highly specific for one virus, are ineffective against virus strains that become resistant to them, or have adverse effects on patients.

http://www.ll.mit.edu/news/DRACO.html

Edit: Thanks to Ygggdrasil:
Rider TH, Zook CE, Boettcher TL, Wick ST, Pancoast JS, et al. (2011) Broad-Spectrum Antiviral Therapeutics. PLoS ONE 6(7): e22572. doi:10.1371/journal.pone.0022572

 

[Ygggdrasil]

Here's a link to the (freely available) scientific paper describing the antiviral strategy:

Rider TH, Zook CE, Boettcher TL, Wick ST, Pancoast JS, et al. (2011) Broad-Spectrum Antiviral Therapeutics. PLoS ONE 6(7): e22572. doi:10.1371/journal.pone.0022572

My analysis of the paper:

Many viruses, during their replication phase, create fairly long double-stranded RNA (dsRNA) molecules. For example, the influenza virus copies its genome through a dsRNA intermediate. In contrast, mammalian cells usually do not produce many long (>~23nt) dsRNA molecules. Therefore, the presence of long dsRNAs inside the cell are a good indicator of viral infection. Indeed, many cellular antiviral defenses are based on the recognition of dsRNA.

In the paper, the authors create a class of protein-based agent (called DRACOs) that senses double-stranded RNA (dsRNA), and when the protein senses dsRNA, it tells the cell to undergo apoptosis, programmed cell death, in order to kill the cell before the virus can copy itself. These DRACOs are able to enter cells in culture and protect the culture from infection by a variety of viruses (the study tested 15 viruses from a variety of virus families). The DRACOs also do not seem to be harmful to uninfected cells (the study tested 11 lines of cultured mammalian cell).

These DRACO agents do seem like they could show some promise, although more research need to be done to determine how effective they will work in patients (versus just in cultured cells). Because the DRACO agents are proteins, they are very susceptible to degradation by the body. I have doubts that systemic application of these proteins into a patient would deliver enough of them to the infected tissue to help control the infection.

Because the DRACOs are engineered from components of the cell already used to combat viral infections (dsRNA sensing proteins and proteins that induce apoptosis), there is some concern that some of the mechanisms that viruses have evolved to evade the cellular antiviral defenses may also be effective against the DRACOs. For example, some viruses have evolved ways to prevent apoptosis (cytotoxic T-cells help fight infection by telling infected cells to undergo apoptosis). However, these DRACOs activate the apoptotic pathway fairly directly and may be able to get around some of the tricks viruses use to inhibit apoptosis. A larger concern are the tricks that viruses have evolved to mask their dsRNA from detection in the cell.

Finally, although the authors show efficacy against a broad spectrum of viruses, not all viruses produce long dsRNAs that can be recognized by the DRACOs. Retroviruses like HIV do not contain long stretches of dsRNA that would activate the DRACOs, so the DRACOs would likely be ineffective against this class of virus.

 

[thomasdalton]

Finally, although the authors show efficacy against a broad spectrum of viruses, not all viruses produce long dsRNAs that can be recognized by the DRACOs. Retroviruses like HIV do not contain long stretches of dsRNA that would activate the DRACOs, so the DRACOs would likely be ineffective against this class of virus.

I don't usually reply to posts but had to correct the invalid conclusion above. DRACOS do not specifically have to use long dsRNA to recognize pathogens. The article quoted did indeed emphasize the use of dsRNA, however the overarching principal of DRACOs is the presence of an unnaturally occurring combination of a pathogen detection domain and an effector domain that performs a prescribed function, one such function being initiation of cellular apoptosis. In other words dsRNA binding is one instance of a detection domain, and cellular apoptosis is one instance of an effector domain action. It would take a couple of pages to list all the possible detection and effector domains so I'll just references the patents indicated in the PLoS ONE article, in particular US 7566694 B2. In reading the patent, you'll also notice that among the spectrum of susceptible pathogens are the retroviruses such as HIV and human T Cell leukemia virus.

 

[Curious3141]

I haven't read the paper, but I am aware that mammalian cells can already detect and react to dsRNA. TLR-3, a class of Toll-like receptor responds specifically to dsRNA. The effector arm involves the induction of interferon production.

 

[Ygggdrasil]

I don't usually reply to posts but had to correct the invalid conclusion above. DRACOS do not specifically have to use long dsRNA to recognize pathogens. The article quoted did indeed emphasize the use of dsRNA, however the overarching principal of DRACOs is the presence of an unnaturally occurring combination of a pathogen detection domain and an effector domain that performs a prescribed function, one such function being initiation of cellular apoptosis. In other words dsRNA binding is one instance of a detection domain, and cellular apoptosis is one instance of an effector domain action. It would take a couple of pages to list all the possible detection and effector domains so I'll just references the patents indicated in the PLoS ONE article, in particular US 7566694 B2. In reading the patent, you'll also notice that among the spectrum of susceptible pathogens are the retroviruses such as HIV and human T Cell leukemia virus.

Considering the authors define DRACOs as Double-stranded RNA (dsRNA) Activated Caspase Oligomerizers, the name implies using dsRNA binding as the detection domain and cellular apooptosis as the effector domain action. I agree that the concept could be broadened to potentially combat other types of pathogens, but these applications to the best of my knowledge have not yet been demonstrated.