Comments on: Pushing viruses over the error threshold

By: profvrr

profvrr — Tue, 19 May 2009 04:16:32 +0000

Yes, ribavirin is the same drug that we have been talking about. It is
not licensed for use in treating influenza, hence it's called
'experimental'. It is licensed for use in treating RS and HCV in the
US. Note that it is 'over the counter' in Mexico where it is used for
treating flu. But it has at least five different mechanisms of action,
not just pushing viruses over the error threshold. It could work that
way with influenza, but it hasn't been looked at.

By: profvrr

profvrr — Mon, 18 May 2009 21:16:32 +0000

By: trine

trine — Mon, 18 May 2009 11:52:31 +0000

Vincent,
So today in the NYTimes, the story about the assistant principle who died of swine flu said he had been given “the experimental drug” ribavirin. This must be the same stuff you are talking about here, right? So the thinking about how it would work is that it pushes the virus over the error threshold once an infection has started?

From the NYTimes: “Mr. Wiener, 55, had been “overwhelmed” by the illness, despite beginning a course of treatment with an experimental drug, Ribavirin, after he failed to respond to other antiviral drugs, according to Ole Pedersen, a spokesman for Flushing Hospital Medical Center, where Mr. Wiener had been a patient since Wednesday.”

By: Increased fidelity reduces viral fitness

Increased fidelity reduces viral fitness — Fri, 15 May 2009 21:46:59 +0000

[...] in complex environments. The isolation of a poliovirus mutant with an RNA polymerase that makes fewer errors during replication made it possible to test this [...]

By: trine

trine — Fri, 15 May 2009 16:32:36 +0000

Hi Vincent,
Are there substances found naturally that act like ribavirin, pushing up the number of mutations per genome?
Thanks! T

By: profvrr

profvrr — Fri, 15 May 2009 12:51:14 +0000

Individual viruses emerge after selection, but they are not the target
of selection. The target for selection is the entire population.

By: profvrr

profvrr — Fri, 15 May 2009 12:51:07 +0000

In some systems it is necessary to accelerate the mutation rate,
particularly for DNA based organisms with error correction. But for
RNA viruses, all the mutants you ever need is in a tube of virus. All
you need to do is devise a selection scheme.

Ribavirin is used clinically to treat many viral infections, but there
are side effects - because the drug is not specific for viral
polymerases, as you point out. Many other base analogs are available,
particularly for treatment of AIDS. Acyclovir, for treatment of herpes
simplex infections, is very specific because the drug is activated
only in cells infected with the virus.

By: profvrr

profvrr — Fri, 15 May 2009 12:50:00 +0000

Great question. Yes, there is indeed a threshold for synonymous
mutations. Two recent papers have shown that for poliovirus. Check out
"Modulation of poliovirus replicative fitness in HeLa cells by
deoptimization of synonymous codon usage in the capsid region" at
http://bit.ly/15K00K.

By: profvrr

profvrr — Fri, 15 May 2009 12:31:39 +0000

By: Dunbar

Dunbar — Fri, 15 May 2009 11:57:48 +0000

Your last comment is puzzling to me. The unit of selection is individual mutants, at the very least.
To Corey, ribavirin is used clinically (http://en.wikipedia.org/wiki/Ribavirin). To gsgs, I don't see why there wouldn't be a synonymous mutation threshold given that the hosts have codon biases.

By: gsgs

gsgs — Fri, 15 May 2009 06:56:55 +0000

is there also a threshold for synonymous mutations ?

By: Corey Philipp

Corey Philipp — Fri, 15 May 2009 00:00:22 +0000

Does the history of viral mutagens mirror those of the animal and bacterial worlds. At first we didn't have the wonderful compounds to speed up the mutation rate and we had to have poor graduate students look for mutation at the normal rate? I know that in Drosophila there was a time when you would do an F1, F2, etc crosses and continue to look for the deviation from the wild type until you found your mutant. Then mutagens like UV light, x-rays, drugs, etc were used to greatly speed these processes up. Likewise, do virologists use high energy photons to mutate viruses or does that not work so well? It seems like you could blast a plaque, once you have one, with x-rays and get viral mutants. Of course if you blast a viral infected cell culture with x-rays you might get some other results because of the damage to the host cell genome.

Also, can ribavirin be used as an antiviral and are there other drugs that could be used as an antiviral that would modify rna dependent polymerase activity? It seems like there could be nonspecific interference with the host cell rna polymerase if you were to administer ribavirin to humans. I guess the trick would be to find drugs that would cause rna modifications to only those rna’s made by rna depdent polymerase. That may not be possible since one rna looks like the other.

By: profvrr

profvrr — Thu, 14 May 2009 18:02:49 +0000

The G64S mutant was selected by growing virus in the presence of ribavirin. The drug selects for pre-existing mutants in the quasispecies. So yes, it's a product of the natural process I've been writing about. Tomorrow I'll write about how this mutant was used to test the theory. Yes, it's been done.

By: Mauricio Carrillo-Tripp

Mauricio Carrillo-Tripp — Thu, 14 May 2009 14:13:35 +0000

Where did this G64S mutant come from? was it just a product of the natural process you've been talking about?

“Now that we have an RNA polymerase that makes fewer errors, we can use it to limit viral diversity and test the theory that viral populations, not individual mutants, are the target of selection.” Wow, has this been done?