Originally posted by: NanoStuff
Originally posted by: BD2003
How exactly are you going to get into the nucleus of a cell *without destroying it* to deactivate (by methylation or otherwise) a specific sequence? Not only that, but how are you going to *find* all the cells that have HIV Proviral DNA in the first place, and not only that, but find them without destroying tissues in the process? And how are you going to prevent the immune system from doing something about it when you try?
Good questions, they all have answers. Molecules constantly get in an out of the nucleus without destroying it, the first one isn't even an argument to be made.
Sure, its no problem at all to get a molecule into a cell. No question about that. But a molecule is JUST a molecule. Its not going to accomplish much. The biggest effect a single molecule can have on a cell is to send a signal, to have the cell "act" a certain way. But the molecule is *just* a signal. The cell "decides" what to do based upon predefined instructions in the genome. And there is no instruction the cell can receive via a single molecule thats as specific as "comb through your entire genome and splice out sequence AGCGT....".
To use an analogy - when you see a yield sign, it triggers you based upon your understanding of driving a car to slow down, look around, determine the appropriate action etc - the sign itself does not contain specific instructions as to how exactly to do it. That would take paragraphs to explain in fine detail, and thats the kind of detail needed to excise a specific sequence from your DNA.
As for finding cells,
http://en.wikipedia.org/wiki/Gene_therapy
I'm not going to rephrase what's already there, just read it. Generally, the idea is that if you engineer a certain protein to bind to another, that protein will only bind to it's match. You use a certain chosen delivery vector in large quantities and the drug will find it's target. You can be selective about the cell type, and such selectivity is improving, but for HIV it would be more of an all-out offensive.
Experimental gene therapy is why I said that its a much easier job to get DNA in than it is to get DNA out. Hijack a virus, and have it insert the DNA that you want. The DNA containing the proper sequence for a working gene that will produce the deficient protein.
Gene therapy doesnt *remove* the "faulty" gene though, it just adds a new, "working" one. Its comparatively easy to make a cell make a specific protein that you desire, hell, its the basis for modern biotechnology.
However, its incredibly difficult to get it to stop making a protein that you dont desire - because thats the ultimate goal here. And when your target is an unknown sequence, in an undetermined place, as you would get from the proviral DNA of a rapidly mutating virus, its at the moment, insurmountable.
And unfortunately, the immune systems idea of a cure for a cell that has foreign DNA present is not to excise the DNA - the cell itself can't really tell where it is, since molecules lack intelligence. Its to kill the entire cell. Hence the shutdown of the immune system in advanced AIDS - your immune system is killing itself concurrently with the HIV killing the immune system.
From wiki:
HIV differs from many other viruses as it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 109 to 1010 virions every day, coupled with a high mutation rate of approximately 3 x 10-5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.[55] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[55]
Even if you could hypothetically engineer a magic molecule capable of doing all the things that are pretty much infeasible in a living cell, let alone an entire body, it would never even be able to keep up with the rate of mutation.
Once that viral DNA is in the genome, its there to stay. Seriously. Its impossible to fully remove. The viral particles can be attacked in order to slow replication and hold the virus at bay, as is the focus of current research - but thats no cure.
For something to be considered a total cure, even if it couldnt excise the proviral DNA, it would at least have to make sure that the virus is stopped in its tracks before it forms full viral particles and lyses the cell to release them.
Gene therapy could theoretically (VERY theoretically) come into play to accomplish this in several ways, but none of them are simple and it would take a whole book to go into how complicated it is. But even the simplest form of gene therapy, adding in a functional gene, a known, specific sequence, to alleviate a protein deficiency is not clinically viable yet. By comparison, the genome modification needed to insert enough information to deal with the products of a rapidly mutating virus is not even in the same galaxy.
It's not impossible because you don't understand it
I don't understand it myself but there are people that do.
I'm in my senior year as a cytotechnologist. This doesnt make me a medical researcher per se, but lets just say I know my cells, viruses and genetics better than most.
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