Tuesday, 23 October 2012

Restricted access (post 1 of 2)

 A lot of my blog posts recently have been on viruses since this is where my main scientific interests lie (and much of my knowledge). However, there’s so much more out there in science and not everyone is as interested in virology as I am, so I like to mix it up where possible. I had originally intended this post to have nothing to do with viruses, but then an article caught my eye. I’ve now postponed leaving the virological topics, for a little while, to talk about a new discovery because I think it’s very cool.

Illustration of the HIV life cycle. This is a nice simple image to use
with my explanation in the text, but I do want to point out that the
virus does not infect the same cell it has come from as this would imply
The above-mentioned article was published on the 23rd September on Nature online and is still awaiting publication in the printed copy of the journal. The work in the paper is by Michael David’s lab at University of California, San Diego and centres around the discovery of a novel HIV restriction factor. I’m sure everyone reading will know a bit about HIV (I’ll get to restriction factors shortly) however, I’d just like to make sure everyone is one the same page. HIV is a retrovirus; this means it has a genome made of RNA, a molecule that is very similar to the DNA that makes up our genome, but has a slightly different sugar. The virus enters into cells and converts its RNA genome into DNA through a process termed ‘reverse transcription’. This viral DNA is then inserted into the DNA of the host cell, like sliding an extra card into a deck of cards. The infected cell with inserted HIV genetic material is unaware of the deception and treats the viral DNA as any human DNA and produces the proteins it codes for. These proteins then form new viruses and allow the infection to spread within and between individuals. In the most basic possible sense the HIV life cycle therefore has five main steps: entry, production of DNA, insertion of this to the host genome, production of proteins, and exit from the cell to spread the infection.

While I’m sure most people know of HIV, I imagine less will have heard of restriction factors. Restriction factors are a collection of aptly named proteins that function to restrict the life cycle of viruses. The majority of known restriction factors target HIV, though proteins have been found that target other viruses. For the time being I will focus on HIV, but will also touch on some other viruses later on. The first HIV restriction factor discovered has the highly catchy name of APOBEC3G. Shortly afterwards the protein tetherin was discovered, followed by TRIM5a and SAMHD1. Each of these proteins has the ability to block the HIV infection at different stages in its life cycle.

The APOBEC3G protein acts early in HIV infection, though there is still debate as to exactly how. The protein has the ability to directly mutate the HIV genome when it is initially converted from RNA into DNA. The level of mutation introduced is so extensive that it is termed ‘hypermutation’. This hypermutation means that the HIV DNA would either be destroyed or, once integrated to the host cell, would be defective in producing the proteins needed for spread of infection. This is how APOBEC3G was initially thought to function. However, it now appears that the protein may simply inhibit reverse transcriptase (the HIV protein that switches RNA into DNA), and thus block infection of the cell without directly causing mutation. Either way, APOBEC3G has the ability to stop infection by blocking at the step of reverse transcription.

While APOBEC3G targets a process early on in the HIV life cycle, tetherin targets right at the end. Tetherin does as the name implies and functions to tether viruses to the cell. When new viruses are produced they need to leave the cell in order to spread infection. For some viruses they simply cause the cell to burst, thus allowing exit, however HIV uses a much less drastic approach through its use of the cell’s natural mechanisms of export. Tetherin sits in the cell membrane and grabs on to any HIV viruses that try to leave, thus preventing spread of infection. Think of this as someone grabbing your arm as you walk out the door.

An image of tetherin in action. Taken directly from Neal et al. Nature 451 (2008) - the paper that had the original discovery of the protein. The main image to look at is the box labelled G, the small black dots are HIV particles, and the big grey bulge is the cell. You can see that tetherin is holding HIV particles to the cell and blocking their escape.
Next we have TRIM5a, which perhaps I shouldn’t technically include when talking about HIV restriction factors. TRIM5a functions by binding to a virus when it first enters the cell and begins uncoating (see the above image of the life cycle). It is unclear how, but this process disrupts the initial stages of the life cycle meaning the cell is never properly infected. The reason that TRIM5a shouldn’t be included is that it does not bind to HIV, in humans at any rate. The interesting thing about TRIM5a is that in Old World monkeys it is able to block HIV infection and the addition of a single mutation to human TRIM5a leads to the same effect. If that mutation were to naturally occur to TRIM5a then it may well be able to block HIV infection, but for the time being, in terms of HIV, it is completely useless (it does protect us from other retroviruses however). 

The final restriction factor to discuss, as background, is the most recently discovered, SAMHD1. This protein inhibits HIV infection of certain cells by depleting the pool of available molecules to make DNA; it essentially starves HIV meaning it is unable to cause infection. SAMHD1 is a pretty good restriction factor unlike the others (which I’ll get to in a minute) as HIV rarely infects the cells that express it, unfortunately not many do.

Now with all of these defences you may be wondering why HIV infection happens at all. That brings us a fact that I just alluded to in that these factors don’t really work. HIV is able to cause infection since it is has the ability to subvert our defences. There is a constant battle between our cells and HIV, we evolve a defence then HIV evolves to block the effect of that defence. Since HIV evolves much faster than our cells the virus constantly has the upper hand. The HIV proteins Vif and Vpu have evolved to cause degradation of APOBEC3G and tetherin, respectively, meaning they simply have no effect on the virus. TRIM5a as I have mentioned has no effect on HIV and this is simply through mutation of the virus at the point the protein would bind to, thus blocking its ability to have any effect. We are yet to find a countermeasure to SAMHD1 but there may not be any need since it is expressed in so few cells. While we have evolved these defences to infection that work nicely when studied in a lab, in the real world HIV has one up on us through its countermeasures.

The lack of effect of these factors is obvious based on how many people have HIV infections, however that does not make them pointless to study and discover. The hope is that if we further our understanding of natural restriction to HIV we may be able to produce drugs that work in a similar way. For instance, if we could produce a molecule that functions in the same way as tetherin, but is insensitive to Vpu then this may have therapeutic use in tackling HIV. Therefore extending our knowledge of these factors, and finding more, is essential in our fight against HIV, and other viral infections.

So that sets the stage… I don’t like these blog posts to be overly long so I’m going to leave this post here and come back with a second part talking about the newly discovered restriction factor human schalfen 11. In keeping with the restriction factor theme I then plan to write a blog on another very interesting protein IFITM3. So make sure you come back for those…

No comments:

Post a Comment