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Innate Immune Response to HIV

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mecch:

--- Quote from: Mishma on February 16, 2013, 02:26:10 PM ---Neuroimmflammation has been the bane of my existence since I first became aware of my symptoms of HIV infection, some 28+ years ago.

--- End quote ---

How does this manifest?  Neuropathy?

Mishma:
Auto-immune encephalitis in the CNS and Motor Predominant Polyneuropathy with conduction block in my peripheral nervous system.

I'm in remission for other auto-immune diseases: Thrombocytopenia and Hemolytic Anemia and Graves disease.

If you guys and gals don't mind (since my mind is going) I'm going to keep posting to this thread articles of interest that involve our innate immune response, which has been given short shrift not only in these forums, but within the larger medical community as well. Even the latest gene targeting technology (superior to the synthetic zinc finger nucleases) comes from new work involving our innate immunity research. 

oksikoko:

--- Quote from: Mishma on February 20, 2013, 12:35:34 AM ---If you guys and gals don't mind (since my mind is going) I'm going to keep posting to this thread articles of interest that involve our innate immune response, which has been given short shrift not only in these forums, but within the larger medical community as well. Even the latest gene targeting technology (superior to the synthetic zinc finger nucleases) comes from new work involving our innate immunity research. 

--- End quote ---

I certainly don't mind. What I can understand is fascinating. I only wish I had started reading about this earlier. It's like a foreign language, and I'm far beyond optimal age, unfortunately. Do you understand all of this?

In the most recent abstract you posted, I lost the thread after "Golgi-associated plant pathogenesis–related protein" but found it after "GAPR-1 is an endogenous inhibitor of autophagy." I mean, I know what all of those words mean except Golgi, and it's been around for over 100 years, so there's really no excuse. If you'll indulge me, let me try to put this in layman's terms without reading your synopsis, which would be cheating. One step at a time:

OK, so part of our immune system concerns itself with "eating" our own cells during nutrient scarcity. This is called, naturally, autophagy, and the things that do it are called autophagosomes (auto [self] phago [eating] somes [bodies]).

You wouldn't want this process to be unregulated, because, much as unregulated cell division causes cancer, unregulated cannibalism would lead to the untimely death of the organism. So, we have this nice thing called a Golgi-associated plant pathogenesis–related protein 1, or GAPR-1 for short. The Golgi is an organelle (chic!) which is similar to the dude who boxes your purchases before Amazon ships them to you, except it packages up proteins before they leave the cell. Pathogenesis has to do with the origin of disease, but what "plant" has to do with it is beyond me. Let's just accept that GAPR-1 is a protein that works at the Golgi and smokes cigarettes out back on its lunch break. Whenever GAPR-1 is mucking about, autophagy seems to slow down, which is something we noticed when we knocked GAPR-1 down in HeLa cells, whatever those are, and saw an increase in the number of autophagosomes running around free in the cytoplasm. We aren't entirely sure why, but inspection under a microscope, shows that beclin-1, a real high class autophagosome, likes to slum behind the Golgi smoking cigarettes with GAPR-1 instead of eating cells. If you ask me, it's afraid to eat because GAPR-1 makes horrible comments about its figure, but I'm not one to gossip. In any event, it's important to remember that this is not necessarily bad, since we don't want unregulated autophagy, nor do we want to interfere in their relationship, however codependent it may be.

Back to our story. In times of plenty, autophagy serves not only as a way to recycle nutrients but also kicks in as an immune response against cells which have been invaded by foreign bodies. HIV is a tricky little bastard, though, and has a defense against autophagosomes: one of its proteins, Nef, binds to the aforementioned beclin-1. With the cells supply of beclin-1 bound by HIV or occupied by GAPR-1, the total amount of autophagy goes down and the viral invader continues replicating in compromise (and uneaten) cells. Oh, noes!

Shoji-Kawata and his buddies used a fancy method to figure out where HIV-1 had bound beclin-1. With this information and an HIV protein called Tat, they reverse engineered something called Tat-beclin-1. It's similar to beclin-1, but has the figure of someone who never gave birth to four kids and who gets weekly botox treatments. There's also something called "tat-scrambled" though I don't get its relevance to the plot, so I'll ignore it.

So, GAPR-1 finds this Frankenstein peptide, Tat-beclin-1, irresistible and starts smoking with it instead of plain Jane beclin-1, who frankly should hit the gym more. Beclin-1 is completely torn up by this and spends its evenings bingeing on virus-flavored cells and old Bette Davis movies. So by pimping Tat-beclin-1 out to GAPR-1, we can indirectly increase the number of virus-infected cells that get eaten.

Shoji-Kawata and his pals tried introducing Tat-beclin-1 into cells of healthy mice, and it reduced replication of consequently introduced viruses. Ones you've heard of, like West Nile, and ones you can't spell, like chikungunya. There seem to be no toxic effects, so they're guessing this will work in people to increase overall autophagy, decrease overall viral replication and increase survival rates.

Please tell me something here is correct. If nothing else, it's made me want Haagen Dazs, and it's nearly time for Stribild. Stribild loves fat, and I so rarely give it to him. Everyone wins except science.

The end.

Mishma:
Outstanding synopsis! You did a heck of a lot better than I did in describing this process and paper. And of course it is a specialized language. There are articles in Science and Nature that are  way outside my field and, in general, I don't have a clue what they are talking about.

 Do I understand all of it, heck no, primarily since I've been out of academia now for over 8 years and the field is evolving rapidly. Also because I don't subscribe to the journal and only get the abstract via my subscription to Science Magazine.To fully comprehend the results you would have to study the methods and other sections of the full paper

A great deal of redundancy is build into our immune system which HIV seems to be able to circumvent. Autophagy and Apoptosis, to my mind, is the systems option of last resort and it too seems to be thwarted in many cells, for a variety of reasons.

If you haven't already try tackling that review I posted further up the post. As a review it is a little more digestable than this paper.

mitch777:
Please pardon my intrusion into this thread, but I can't help myself in commenting on Oski's "story".
Scientific research is beyond my pay grade. ???
The character development and personal antidotes had me rolling on the floor.
I still don't understand it and will have to wait for the movie to come out.
Thanks for the laughs! :)

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