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).
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.