Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

July 29th, 2010

Genetic ironies: Retrovirus version

I’ve mentioned the APOBEC family before (for example, here and here). They’re a group of mammalian genes that (among other things) protect against retrovirus infection.

DIfferent strains of mice have different resistance to retrovirus infection. Some strains are highly resistant, others quite susceptible. At least some of this difference in susceptibility comes down to different expression levels of mouse APOBEC3: High expression of the gene gives good resistance to some retroviruses, low expression gives less resistance.

How come some strains have higher expression than others? Turns out that it’s because a retrovirus inserted in the APOBEC3 region of the genome of certain mouse strains, and that insertion cranks up expression of the APOBEC3.

We discovered that the mA3 allele in virus resistant mice is disrupted by insertion of the regulatory sequences of a mouse leukemia virus, and this insertion is associated with enhanced mA3 expression.  ((Sanville, B., Dolan, M., Wollenberg, K., Yan, Y., Martin, C., Yeung, M., Strebel, K., Buckler-White, A., & Kozak, C. (2010). Adaptive Evolution of Mus Apobec3 Includes Retroviral Insertion and Positive Selection at Two Clusters of Residues Flanking the Substrate Groove PLoS Pathogens, 6 (7) DOI: 10.1371/journal.ppat.1000974))

So perhaps low APOBEC expression allowed retrovirus infection, which led to insertion of the retrovirus genome, which increased APOBEC3 expression and provided resistance to further retrovirus infection.

July 26th, 2010

Quasispecies thoughts

Quasispecies theory predicts that slower replicators will be favored if they give rise to progeny that are on average more fit; these populations occupy short, flat regions of the fitness landscape … Flat quasispecies accept mutation without a corresponding effect on fitness … A flat quasispecies with an expansive mutant repertoire can explore vast regions of sequence space without consequence and is poised to adapt to rapid environmental change.

Lauring, A., & Andino, R. (2010). Quasispecies Theory and the Behavior of RNA Viruses PLoS Pathogens, 6 (7) DOI: 10.1371/journal.ppat.1001005

(My emphasis)  RNA viruses in general form quasispecies because they have such high mutation rates.  Many (though by no means all) emerging infections are the result of RNA viruses. I’ve pointed before to aspects of viruses that might help them jump from species to species (for example, here — though this is a DNA virus, not an RNA virus, and I don’t think it runs in quasispecies — and the string of posts I link to inside that one).

One example Lauring and Andino point to is influenza virus hemagglutinin (HA). Influenza mutates very rapidly, of course, but most of the changes are harmful to the virus. But changes in HA seem to be very well tolerated. Since HA is a major target of the immune system, this property allows influenza to avoid the immune system without getting hit by defects in fitness associated with the immune evasion.  This is a contrast to, say, HIV (generalizing here! This isn’t always true). HIV within a patient undergoes constant changes to avoid the immune response, but many of these changes reduce the overall viral fitness. If you take the mutated HIV into an environment without that particular immune response, the virus quickly mutates back to its original, more-fit, form.

I’m not sure how we would assess, in advance, which viruses are more “flat” than others and that are therefore more able to adapt to new species, but it’s something to think about as we look at new viruses and new viral variants. I would be interested in SARS, for example — what happened to mutation tolerance as the virus adapted to humans? Was the virus that originally jumped into humans different in this was from the ones that normally infect bats? Not easy to measure, though.

July 14th, 2010

Forgotten pandemics

America's Forgotten PandemicI’ve been going to some influenza-related conferences in the past week, including the International Conference on Emerging Infectious Diseases in Atlanta.  One of the topics that’s come up several times is the public awareness of the 2009 pandemic H1N1 — there’s a general sense that the general public has lost interest in, or even is actively contemptuous of, the influenza pandemic.  This is causing a lot of frustration, and some bafflement, among the fairly specialized audience here.

I don’t have any particular insights into this, but it’s striking to me that there may be some parallel to the vastly worse 1918 pandemic.  Like 2009, the 1918 flu did virtually all its damage in the USA in less than a month, around October of 1918. (The difference, of course, was that in 1918 the virus killed far more of the people it infected.) In spite of the huge number of deaths that virus caused, though, it seemed to quickly recede into people’s memory as well.  I refer you to Alfred Crosby’s history of the outbreak (Amazon link), which is actually called “America’s Forgotten Pandemic: The Influenza of 1918″, for  a much more detailed discussion.

Is there something about these sort of explosive, but short-lived, outbreaks that lets them be easily replaced in peoples’ anxiety closet?

July 12th, 2010

Short takes: Deep sequencing and HIV drug resistance

Short comments about what I’ve been reading (besides several hundred influenza articles):

Hedskog, C., Mild, M., Jernberg, J., Sherwood, E., Bratt, G., Leitner, T., Lundeberg, J., Andersson, B., & Albert, J. (2010). Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011345

The whole deep sequencing thing is going to profoundly change our knowledge of viral pathogenesis, as well as their ecology.

With highly mutation-prone viruses like HIV, hepatitis C virus, or influenza, our understanding of genome sequences has been based on the overall average genome — the average of a vast and diverse population. That average, that we’ve been calling the genome of these viruses, may not even exist as such, and certainly the minor variants that have been missed by traditional methods are also critically important, because they can explode out within a few days to take over the entire population, given the right set of circumstances. For example, if among those minor variants there are a few drug-resistant strains, then as soon as you treat the host, those variants may be able to take over.

In this paper, deep sequencing of people with HIV shows that drug-resistant variants do exist even before treatment, but they are normally very rare. They can take over during treatment with the particular drug, but when treatment is stopped they rapidly regress to rarity. This is presumably because the drug resistance makes the virus globally less fit (in the natural selection meaning of the term). When their more-fit brethren are destroyed by a drug these crippled, but drug-resistant, variants can grow out, but remove that selective pressure and the more wild-type versions take over once again.

As well as implications for treatment, this tells us something about viral reserves:

In most patients, drug resistant variants were replaced by wild-type variants identical to those present before treatment, suggesting rebound from latent reservoirs. 1

  1. Hedskog, C., Mild, M., Jernberg, J., Sherwood, E., Bratt, G., Leitner, T., Lundeberg, J., Andersson, B., & Albert, J. (2010). Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011345[]