The idea of discussion questions is to propose some ideas you might like to discuss in class (and to show you read the paper!). Conceptual, strategic questions are somewhat preferred, but it's also OK to post questions like "what does the y axis on Figure 2 really represent?" or "I don't know what 'transorthogrification' means. I spent some time looking for it on the web, but I'm still having a hard time with the concept. Can anyone help?"
Thursday, September 24, 2009
first post: Mittler
Please enter discussion questions as comments ... as mentioned in the e-mail,
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Posted on behalf of Iwan Molgo (sent by e-mail before I got the blog set up):
ReplyDeleteNice article,
A little bit old but still really interesting. I came up with a question that we maybe can not answer, but if you inject non infected mice/ human with a vaccine. That has the symptoms of the 6 week stage of infection or different HIV strains. Would this procedure give the mice/ human immune system more time to make anti-bodies against these various strain that will be developed over time when one may get infected. As it seems in one of the hypothesis, was stated that the HIV mutation is always a step ahead. So your body will be a step ahead before infection may occur
I do not know what they use nowadays, but multiple drug dosage seems to be a very dangerous. Even though there will be drugs against this virus, mutation are constantly going to take place. The problem is that people are spreading the virus without knowing it, so it is difficult to develop drugs for every kind of mutation. Completely distroying the virus could be possible, but can our body regenerate the affected organs or Thymus?
How could a "structural change" determine the steady-state abundance of HIV/CD4+ T-cells? What do they mean by "structural change"?
ReplyDeleteCould predictions about macrophage dynamics help to better explain the slow decline of CD4+ T-cells?
Kristen
My question is similar to Iwan's, in the sense that I wonder if the virus could be eliminated if the host was treated in a very early stage of infection, given the high mutation and recombination rate of the virus. For instance 6 to 9 weeks after he gets the virus?
ReplyDeleteThis is a very interesting new and comment,it shows how science was focusing research efforts for understanding HIV dynamics, and drug treatments!
ReplyDeleteAccording to the paper, I am wondering why was "the chemical war" against virus the best formula to understand the virus dynamics, It make me think that crop "pests" could have a similar dynamic model! There are agronomists looking for understanding how to control the "pest" in crops too! Could HIV spread in the body such a "pest" do in crops?
I would like to bring a recent new about HIV research! They have found hope in new antibodies:
http://www.sciencemag.org/cgi/rapidpdf/1178746v1.pdf
but, is it possible that the cure for AIDS/HIV will come from a natural and random mechanism? is there enough time for humanity? will humans ever understand that one of the most important weapon against HIV is knowing that if they have the virus by HIV test, for avoiding the problem of spreading the virus without knowing it?
From Christine Holdredge:
ReplyDeleteI'm interested in the post treatment virus/ CDk4+ cell dynamics (Fig. 1b, Mittler). It seems amazing to me that the pre- and post-treatment steady states are essentially the same, even though the virus dynamics have been dramatically changed. By this I mean, prior to treatment there is tremendous genetic variation in the virus (based on my understanding from reading), but after treatment variation has been greatly reduced since only drug resistant mutants persist in the system. Wouldn't you expect that this change in virus composition would somehow shift the steady state? On a similar note, I found the hypothesis that virus mutation rates outpace CD4+ cell mutation rates and basically overwhelm the immune system over time fascinating. Since the HIV virus is replicated within host immune cells, mutation rates would arise because of host transcription errors, right? So, if the same cell machinery is that reads the HIV virus RNA is reading the host RNA, wouldn't the mutation rates be similar or equivalent?
@Iwan: why do you think using multiple drugs is dangerous? Because it will encourage multidrug resistance? (Actually, MDR is more likely if one (over)uses drugs *sequentially*)
ReplyDelete@Alejo: (1) prevention certainly seems easier than cure, but (a) that doesn't help people who are already infected (the difference between a public-health and clinical view of disease) and (b) easy as it might seem, the evidence is (based on continuing HIV epidemics everywhere in the world) that it isn't *that* easy. (2) I don't think humans are in danger of extinction via HIV. There are mutations that seem to protect against HIV at least partially, but I don't think we can wait for them to spread via natural selection ...
@Christine: because RNA is transcribed to DNA via viral reverse transcriptase (the host doesn't have any), it is extremely subject to errors at this point ... (2) the picture in Mittler is a bit oversimplified -- in general the steady state level after drug resistant mutants arise is about 10x lower than the original steady state.
How does the sell-nonself discrimination function and how could it killed uninfected CD4 cells as proposed by the authors?
ReplyDeleteWhy is the estimation of half life important in this and other studies? What about composite half-life?
1.
ReplyDeleteWhat mechanisms are responsible for regulating T-cell density? I would imagine there is a feedback system of some kind regulating the production of new T-cells. Is it not possible that the HIV virus is directly interfering with this process? Getting an estimate of normal T-cell turnover in healthy individuals would help diagnose deficiencies in infected patients. I saw no mention of non-infected t-cell turnover in the paper, did I miss something?
2.
It would be interesting to compare the response to antiviral treatments at different time points post infection. Fig 1 shows anti-viral treatment administered ~7yrs post infection. It seems as though you would want to target treatment in the periods where viral load in the blood was lowest a) just after infection b) just after viral load decreases at ~6 weeks. It seems like others had the essentially the same comment.
In reference to Mittler et al.: Very interesting (yet unfamiliar) topic. I look forward to reading more papers on this to see which hypotheses in Box 1 have been rejected since 1995. I also found the concept of "latently infected cells" interesting, in that even a successful drug treatment may require lifelong periods of drug dosage to keep the virus suppressed. Do we have any idea of the extent to which the virus may remain latent? Also, this is probably a silly question (and surely outside the scope of this paper), but have their been efforts to transplant CD4* cells from healthy patients or organ donors to make up for the decreased rate of CD4* production that may allow HIV to give rise to AIDS?
ReplyDeleteTravelin' Man = Mike Gil
ReplyDelete@marvin: the idea would be that the immune system would be sensitized to T cells (not just infected T-cells) and would start targeting all T-cells, not just infected ones. We'll talk about half-life a lot more.
ReplyDelete@tim: non-infected T cells last months to years.
Jameson, S. C. 2002. Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2:547-556. doi: 10.1038/nri853.
@mike: you may be disappointed. We know a lot more about how HIV evolves within the host, and the opportunistic pathogen hypothesis is not very well supported, but I haven't run into very many thorough "disconfirming/rejecting" experimental/observational tests. HIV progression is still something of a mystery, as far as I can tell.
ReplyDeleteHello all. Great comments. My questions/comments correspond to some presented already. Most notably the timing of detection and treatment. Would early detection and treatment with an antiviral cocktail do the trick . . . or would it lead to a more rapid progession of the disease? (Iwan, as far as I know multidrug treatments are pretty standard) Like Tim just said, how important is the timing of treatment? Without reading more recent literature which will likely be required during this module and cover some of our questions (hmhmm ... Alejandro), I think this should be a fruitful discussion in terms of "evolutionary" timing.
ReplyDeleteMy other question comes from Box 1. The second hypothesis states that " ... the virus is continually evolving to occupy new niches inside the host". Is there any evidence to back-up this hypothesis? I understand that the onset of AIDS can be quite variable, but what about the effects? Do suffers typically die with similar afflections or do they show variability in condition that would suggest a wide range of viral "niches"?
Pretty scary stuff. I always think of the phylogeny I saw (can’t remember where) of HIV variation within a patient over time. It was strikingly clear that keeping up with this virus is a daunting task. Anyway, my question is a little peripheral to the paper but here goes . . .
ReplyDeleteBasically, I am curious if researchers have fully utilized what we know of the origin of HIV to explore its dynamics. That is, I am under the impression that there is a second, less virulent strain of HIV with a predicted primate origin different from that of the more common strain. What could/has research into its pathogenicity told us about the more virulent form? Second, if HIV is the result of SIV jumping the species barrier has any work been done on SIV strains jumping the species barrier between other primates? This would be playing with fire but presumably we might be able to facilitate this in the lab to, in effect, create a more virulent model system (that is I think most SIV strains are rarely of much effect to their hosts so less informative to our research) . . . it’s a bit late, maybe my moral compass is not quit straight right now :)
Also aren’t we creating more resistant forms by effectively selecting for drug resistance? This is a little bit of a ruse on my part since I have heard it argued that controlling spread between people is the best way of making the virus less virulent. In a society where the spread is curbed the virus must hang on to its host longer to find a new host. On this note overcoming drug resistance is a mute point for most of the world who likely can’t get access to drug cocktails for the rest of their life. Until there is a "cure" prevention would be the key but that’s a whole other topic. I’m sure I don’t have all the facts so I’ll stop here :)
Hi all. Bit of a late post here but wanted to get it out.
ReplyDeleteI am curious about the global virus evolution, it seems that there has been considerable work investigating how the virus evolves within a host and its very rapid ability to respond to strong selective forces, i.e. antiviral drugs. However are we seeing any trends in the overall HIV population toward higher virulence?
I could see HIV's strong ability to adapt changing internal environments posing a major problem in certain parts of the world, such as Africa, where detection of HIV and overall knowledge of its transmission are low. Places like these could serve as hotspots for HIV genomic diversity allowing for a population level shift toward higher baseline virulance and potentially baseline drug resistance.
Info about HIV regulatory genes:
ReplyDeletehttp://www.mcgill.ca/files/microimm/466_gatignol_01.pdf