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Before Christmas I wrote a diary regarding a (then current) news story, which was a partial response to another user's diary regarding the same story. Unfortunately due to the nature of the science I will discuss here you should read those diaries and the news release (I put alot of information regarding basic HIV biology into my diary...and it is unfortunate because it turned out rather long, and somewhat related to what will be discussed here). You can find my diary here and georgia10's diary on the subject here.

The topic of this diary is a Yahoo! news release (find it here) that came out today about an exciting "new" discovery about the interaction of HIV and human cellular proteins. (And I put new in quotes because the original discovery of this interaction was published almost a year ago.)

This area of research is very exciting for a couple of reasons which I will discuss below the fold (and again I anticipate this to be a rather long diary due to the background I will have to cover, sorry in advance).

So to start off with I should explain what is being discussed in the news article linked above. It has long been known that HIV does not very efficiently infect cells from most "Old World" monkeys in culture. Nor does the virus lead to the same immunodeficiency in Old World monkeys, like it does in Humans. However it was also known that HIV infected "New World" monkey cells in culture very efficiently. Also, in many species of New World monkeys HIV leads to a very rapid progression to an immunodeficient state, and a quick death of New World monkeys infected with the virus. (Which is why researchers have had to use SIV/HIV hybrid viruses in their research on vaccines and HIV immunology.)

From this researchers suspected that there was some sort of intracellular protein blocking HIV infection in Old World monkey cells. Extrapolating from this it was theorized that the human form of  this protein didn't interact with HIV nearly as well, and that the form found in many New World monkeys was even worse at this interaction.

Before I fast-forward to February of last year let me go into some HIV biology as a background. The first step in HIV infecting a cell occurs when proteins on the outside of the virus interact with receptors on the outside of a cell (as occurs with every virus). Subsequent to that the membrane surrounding the virus fuses with the cell's membrane (this also occurs with every membrane-bound virus). Then the part of the virus containing the infectious RNA enters the cell. At this point however the RNA is enclosed hollow ball of proteins. To visualize this think of an egg, with the shell being this protein coat and the goodies inside (the egg white and yolk) being all of the other proteins (and RNA) required to get the viral RNA to DNA and into the chromosome where it can start making new virus particles. The protein making up this shell is called either the capsid protein or gag (though gag is truly the immature form which also gives rise to 2 other proteins).

Now, fast-forward to February last year. Researchers at Harvard found that it was at the point where the viral proteins and RNA are surrounded by the capsid protein that the Old World monkey form of the protein, Trim 5 alpha, acts to stop HIV infection. This interaction is believed to target the capsid proteins for destruction. Some of you may be thinking "Who cares, all the other goodies are inside. Why does this matter?" That's a good question, which can be answered (without too much extraneous detail) in the fact that a very specific sequence of events must occur for the incoming virus to infect the cell. This sequence of events includes the native uncoating of the virus. At best the destruction of the capsid proteins surrounding the rest of the virus (mediated by Trim 5 alpha) perturbs this sequence of events, at best it leads to the destruction of the other viral proteins (and RNA) as well.

Whoop-dee-doo. Some researchers found this interaction between HIV and a monkey protein, who cares?

This is a significant finding for several reasons. I will further discuss how this discovery could lead to novel treatments (perhaps a cure) for AIDS, though there are other reasons including developing better systems for developing a vaccine against HIV.

The interaction between capsid proteins of HIV and Trim 5 alpha could lead to a novel target to design an inhibitory drug against HIV. This could be done by finding a small molecule that enhances the interaction between the human form of Trim 5 alpha and HIV capsid proteins. This is important because there are currently no drugs targeting the capsid protein of HIV. The capsid protein is necessarily one of the most stable viral proteins. Most HIV proteins are able to mutate to a form not affected by an anti-HIV drug which targets them, however the capsid protein is rather constricted in its ability to mutate and still yield a protein that is still able to assemble an infectious virus (this is because the capsid protein has to form many interactions during assembly, maturation, and disassembly of the virus). This would add another drug to the existing ones available for treatment of HIV.

However, as mentioned in the news release, this also gives a novel target for treatment by a gene therapy strategy. For those of you who don't know exactly what gene therapy is don't worry, I'll explain it (I only had a basal knowledge before working in the field). The original idea behind gene therapy was treating a variety of diseases (such as cystic fibrosis) caused by a mutation in a gene which leads to either a lack of or a non-functional protein that is required for a normal life. This is done by introducing a normal copy of the mutated gene into cells which should normally express it (in the case of cystic fibrosis, epithelial cells of the lung). This is normally done by modifying viruses so that they are no longer infectious, instead you can make them carry the gene you want to introduce (remember viruses are just genetic information, RNA or DNA, with the associated proteins to turn that information into proteins).

In the study specifically mentioned in the news release (and I'll leave the media bashing for another place but they got the facts wrong), several patients who had severe immunodeficiency syndrome (think bubble boy syndrome) were treated in a study conducted in France. If I recall correctly, 9 patients were treated with a modified HIV virus (used because HIV integrates into the cell's DNA, and is expressed essentially for the life of the cell). 7 of these patients were cured of their immune deficiency (they could live outside of a bubble) however two of them developed leukemia as a side effect of the treatment (the HIV integrated next to a gene [the same in both cases] which normally helps to regulate multiplication of the cell...when the HIV vector jumped into the chromosome next to it this caused the over-expression of this gene, this led to uncontrolled multiplication of the cell and subsequently leukemia). As a side note I should add that many researchers felt it was too early to use such a gene therapy "vector" (modified virus) in such a trial, but the group in France went ahead; with a vector that was even then considered out of date (there is much greater regulation of more modern vectors, and even the possibility to insert a "suicide gene" into the vector incase the person develops a cancer from the treatment the cancer can be controlled).

Back to the treatment of HIV, the group in the press release is suggesting that a similar gene therapy vector could be modified to express a Trim 5 alpha protein which interacts with the HIV capsid protein with a similar efficiency to that of the Old World monkey version of the Trim 5 alpha protein. In a hypothetical world this would lead to a population of cells highly resistant to HIV infection, and could therefore cure patients of the immunodeficiency seen when people infected with HIV progress to full-blown AIDS.

There are many questions yet to be answered and no "cure" for AIDS may develop out of it, but this is an exciting area of research that everyone should keep an eye on. It is one of the most promising strategies for the future treatment of AIDS (though at some point in time I will write a diary on another strategy almost equally intriguing).

As an endnote I should mention that this I am working in this area of research because I find it so exciting (however looking at interactions between Trim 5 alpha and a different virus).

Thanks for bearing with me through the long diary.

Originally posted to Toktora on Tue Jan 11, 2005 at 12:24 AM PST.

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Comment Preferences

  •  Comments/thoughts please (4.00)
    I would greatly like to hear your comments on this issue, even if they are along the line of "why are you posting this crap, it's not even political".

    It helps me the next time I sit down to spend 3 hours writing a diary...what should I include/leave out/cover etc.

    Thanks :-)

    Fighting for peace is like fucking for virginity, only not as much fun.

    by Toktora on Tue Jan 11, 2005 at 12:15:05 AM PST

    •  I'm going to save it...but... (none)
      I would try to make it more readable for a general audience (and perhaps I should take my own advice on the post I just wrote below).  

      I have a pretty good base in chemistry (I'm sure I'll end up majoring in it, along with political science and economics...perhaps I should major in learning to be decisive) and it was still hard to follow at times.  Some kossacks will understand everything, but I'm sure others will be left fairly confused.

      •  That is why I referenced my previous diary (none)
        I tried to simplify things as much as I could so that most people could understand the point of the diary, and yet get the information across. If you could tell me what you're having difficulties following I can rewrite them.

        (Though alot of the topics I discussed were tuched upon in my previous diary, which I think is better. I suggest if you're interrested that you read over that and see if it makes more sense.)

        Fighting for peace is like fucking for virginity, only not as much fun.

        by Toktora on Tue Jan 11, 2005 at 12:35:06 AM PST

        [ Parent ]

        •  naw... (none)
          don't dumb it down at all. It was written so someone with just a rudimentary knowledge of cell biolgy could understand. And it was interesting enough to peak the interest of others, who can check out your diaries or other sources if they want to learn more.

          The ultimate weakness of violence is that it is a descending spiral, begetting the very thing it seeks to destroy--MLK

          by pacific city on Tue Jan 11, 2005 at 12:38:45 AM PST

          [ Parent ]

          •  you're right (none)
            It's hard to fit a ton of information onto one page.  My concern was that people would still (even with the other diaries) be left confused about a lot of the terms.  I probably had my mom in mind.  Someone who hasn't had any bio in 40 years, and someone who doesn't know where to find the simple info (it's not as easy to find as one would initially think).
            •  Just about right... (none)
              You fit a lot of information in a pretty small amount of space and made it simple enough for us laymen to understand (at least vaguely).  

              I have to say I find your type of diary infinitely preferable to those that are unnecessarily flowery and verbose and contain 500 words worth of information within 2000 words of text.  

              Sometimes less is more and you seem to have the balance down pretty well.  

              In Britain they admit to having royalty. In the United States we pretend we don't have any, and then we elect them president.

              by Asak on Tue Jan 11, 2005 at 01:24:47 AM PST

              [ Parent ]

    •  oops... (none)
      what I meant by save is copy it so I can read it later.  I should have been more clear.

      And, I'll use your comment as a tip jar and think this is worth recommending.

    •  As I have said many times (none)
      This is not directly political but good policy decisions are based on a sound knowledge of the "facts".

      Keep it up. It is nice hearing from someone in the field. I'll repost this on Nerd Network News on Sunday.

  •  Interesting/important (none)
    Does this relate at all to the research they are doing with buckminsterfullerene (C60)?

    We learned this in organic chemistry...
    An enzyme that is required for HIV to reproduce exhibits a nonpolar pocket in its three-dimensional structure.  If this pocket is blocked, the production of the virus ceases.  Because buckyballs are nonpolar and have approximately teh same diameter as the pocket of the enzyme, they are being considered as possible blockers.  The first step in pursuing this possibility was to equip the buckyball with polar side chains to make it water soluble so that it could flow through the bloodstream.  Scientists have now modified the side chains so that they bind to the enzyme.

    •  No, not really... (none)
      The capsid protein of HIV is not an enzyme, it is a structural protein. (However it does have a similar organization to that of the buckminster fullerine ~ icosahedral.)

      Fighting for peace is like fucking for virginity, only not as much fun.

      by Toktora on Tue Jan 11, 2005 at 12:31:12 AM PST

      [ Parent ]

  •  wow (none)
    Excellent topic and very well-written. A flashback to molecular biology (but I wish you had written the textbook!)

    Thanks so much for doing this type of research. Finding a cure for AIDS is vital to global security and the prosperity of developing nations.

    Hey, if I was sitting on the board of the NIH I'd give you a grant right now. But I'm guessing your funding is secure? : )

    The ultimate weakness of violence is that it is a descending spiral, begetting the very thing it seeks to destroy--MLK

    by pacific city on Tue Jan 11, 2005 at 12:31:10 AM PST

    •  Actually I'm a graduate student (none)
      So I don't have to worry about my own funding, just that of my boss/advisor (which is very secure).

      Fighting for peace is like fucking for virginity, only not as much fun.

      by Toktora on Tue Jan 11, 2005 at 12:36:27 AM PST

      [ Parent ]

  •  forgiving med? + likely could be an oral drug? (none)
    Thanks for another carefully researched update, Toktora.  Keep up the good work, and good posting on HIV.

    Aside from the possible promise of gene therapy, the potential to develop a drug that isn't "outwitted" by the virus's constant mutations is very significant.  I've done survey and focus group research around issues of drug regimen adherence in HIV.  As you know, extremely high adherence rates are necessary to prevent HIV mutations from defeating a drug.  Most failures of HIV drugs relate back to inconsistent adherence by the patients.  The HIV-positive person then needs to move on to new drugs -- often ones that have worse side effects -- and if they don't eventually nail the adherence challenge, they will run out of options.

    The general public has little idea about how hard it is for the average person to adhere consistently to a drug regimen -- day in and day out for life.  (The same problem exists in patients taking hypertension medicines, for example.)  Research even shows that most physicians are unable to adhere for even a few weeks to a placebo (sugar-pil), in tests of simulated HIV regimens.  A drug that is tolerant of missed doses would be a boon to people living with HIV.  If it were safe, effective, didn't require large doses, and wasn't too nasty in its side effects, it could easily become the main drug used to fight HIV. Or if it requires modest adherence to be effective, a better strategy may be to prescribe it as a patient's second regimen -- once they've been scared by an initial regimen failure.  Most HIV specialist physicians I've spoken with expect most patients to fail their first regimen.  This is the unfortunate fact their experience teaches.

    But here's a question for you.  Is there anyway to know in advance how likely it is that a small molecule could serve to enhance the Trim 5 alpha defense against HIV?  As you probably know, only small molecules can be part of drugs taken orally.  The digestive system can't pass large molecules into the blood, meaning the drug would need to be taken by injection.  For example, the latest new class of FDA-approved HIV medicine, Fuzion (sp?), must be injected.  Any insight you can give on this?

    I look forward to your future diaries on HIV.  Thanks again for your work in writing these.

    Civil society is our collective creation. It's an honorable source of growth, mutual satisfaction and fulfillment. It's yours and mine to nurture, or nix.

    by Civil Sibyl on Tue Jan 11, 2005 at 04:22:22 AM PST

    •  There is no way to really know (none)
      If one specific molecule will act upon and target protein. Technology is thus that a person can look at the target protein and be able to infer what could interact with it in a manner you are looking for (usually blocking the action of that protein).

      That said, what is being proposed is that you find a small molecule that not only interacts with HIV capsid proteins; it also interacts with Trim 5 alpha. Further this interaction should lead to a stronger interaction between Trim 5 alpha and the capsid protein.

      To get a picture on how difficult this could be, let me turn to carpentry for an example. So, let's say you have a board which is a piece of a bookcase. In the first instance you want to remove the board from the bookcase. In this case you have alot of options as to how to do this. You could use a saw, a small hammer or screwdriver (depending on how it is fastened), a crowbar, a sledgehammer, an axe, etc. However in the other case the board wobbles and you want to further secure it to the rest of the bookcase. In this instance you can only use a nail or a screw positioned in such a manner as go through both pieces of wood and thus hold them together. The task awaiting researchers looking for small molecules to strengthen the interaction between Trim 5 alpha and HIV capsid is like finding the nails and screws in Home Depot. They're there, but you're gonna have to look around awhile to find them, and modern technology may point you to a certain area of the have to find the aisle and then the screw or nail you are looking for.

      Fighting for peace is like fucking for virginity, only not as much fun.

      by Toktora on Tue Jan 11, 2005 at 06:09:22 AM PST

      [ Parent ]

  •  Everything is political (none)
    I mentioned in a comment a few days ago that someone recently posited to me that he thought that a new AIDS cure would spark a second sexual revolution, much as the pill sparked the first one.

    It would be a new day for us all, I think, and lead to wholesale rejection of the current REP/conservative position. (Until the inevitable reaction)

  •  Thanks for this analogy. (none)
    Also, the fact that they are searching for a small molecule at least means they think there's a possibility for a non-injected drug to be developed.

    Civil society is our collective creation. It's an honorable source of growth, mutual satisfaction and fulfillment. It's yours and mine to nurture, or nix.

    by Civil Sibyl on Tue Jan 11, 2005 at 03:54:09 PM PST

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