Viruses are tricky monsters. They are little packets of DNA or RNA enclosed in a capsule, and depend on a host to survive and replicate. Once they get inside the host cell, they take control of the host cell machinery and use it to produce more viruses.
Eventually the cell bursts, scattering thousands of copies of the virus into the environment, ready to infect more healthy cells.
Our best defense against viruses are vaccines. But some viruses resist our every attempt to prevent and eradicate them. Notable examples of these are flu viruses and the human immunodeficiency virus (HIV).
Last week, however, a peculiar phenomenon was observed in two siblings: an 11 year old boy and a 6 year old girl. They suffer from a genetic mutation which causes all sorts of tragic conditions- distorted facial features, frequent seizures, hearing loss, and hypogammaglobulinemia (less antibodies in the blood, indicative of a weak immune system).
But they are also much more resistant to viruses, including HIV. If they have less antibodies, and a weaker immune system, then how is it possible for them to have such a high resistance to viruses?
It is because of the nature of the mutation they possess.
Everything in our body is coded by DNA. Our bodies read the DNA and from its information, construct proteins that act as the machinery in all of our cells. If the processes of transcription and translation are foreign concepts to you, read this article about artificial chromosomes. Trust me, you will understand what is going on a lot better once you do. In the coming age of biotechnology, knowledge of the basic functions of our body is absolutely imperative. Those who are armed with this information will be in much better shape than those who do not.
Once proteins are constructed, they are often modified. Links of sugar molecules (called glycans) are glued onto highly specific spots on the protein molecule, giving it additional functions. This is called glycosylation.
The green structure is the protein, while the hexagons represent different sugar molecules
Glycosylated proteins have slightly different shapes, and distinct features. There are many proteins that recognize and bind to glycans, as they form unique, elaborate shapes. Thus, glycans can also act as an identification system for cells.
The entire process is stupidly complex. Do not get discouraged- try and stick through, as it will all come together in one of those “Ohhhhhh!” moments that leaves you feeling grand.
There are two types of glycosylation- N-linked and O-linked. N-linked glycans are found stuck to the amino acid asparagine, while O-linked glycans are found stuck to either threonine or serine. We will not go into the details of the differences between the two, but the type of glycosylation we want to focus on for the purposes of understanding this study is N-linked.
Glycosylation is an immensely complex metabolic pathway involving many steps and many different components (if you don’t believe that, check out this Wikipedia article on N-linked glycosylation disorders).
It sounds simple, as it is essentially just sticking a bunch of sugar molecules onto a protein. But the sugars must be arranged in a precise manner and in many individual steps, each mediated by a different enzyme (an enzyme is a protein that mediates a chemical reaction, such as the binding of one sugar molecule to another or the cutting of such a bond).
First, a fat molecule is synthesized. A chain of sugars is then attached to this fat molecule (called a dolichol) and after many steps of processing, a molecule consisting of a glycan attached to a fat molecule is formed (called a lipid linked oligosaccharide, or LLO).
The first phase of glycosylation. The light blue rectangle is the dolichol, or fat molecule, while the green circles, blue squares, and red triangles are sugar molecules
Yes, the above diagram looks terrifying, but the important thing to note is that a fat molecule from the endoplasmic reticulum has sugar molecules attached to it until the glycan is assembled, and then the glycan is transferred to the protein of interest.
Any defects in the steps above are classified as type I congenital disorders of glycosylation (CDG). The LLO is just a placeholder- the glycan must now be transferred from the fat molecule to the protein of interest, and then trimmed. Another series of disgustingly complex steps occurs to do just that.
The glycan is cut from the LLO and glued onto the protein of interest by an enzyme called oligosaccharyl transferase. It is then trimmed by enzymes called glycosidases.
The second phase of glycosylation involves moving the glycan from the fat molecule to the protein
These glycosidases, particularly glycosidase I, are important. This is because once the glycan has been trimmed by glycosidase I, other proteins bind to it. These proteins, called calnexin and calreticulin, help fold the glycosylated protein into its final shape.
The entire process is like a bald spy getting a hair transplant for a mission. First, hair follicles must be grown from someone who has the right hair for it (analogous to how the LLO is formed- any defect here is a type-I CDG). Next, they must be moved to the spy’s head in exactly the right spots (transferring the glycan from the LLO to the protein). Finally, the hair must be trimmed in exactly the right manner for the disguise to work (like the action of glycosidases).
As you can imagine, if the hair is not trimmed properly the spy’s disguise is useless. No matter how well the previous steps were performed, if the spy looks out of place they will be captured and it will all be for naught. Similarly, a defect in glycosidase I would be fairly catastrophic. Without it, calnexin and calreticulin cannot bind to the glycan, and the protein does not fold properly. The protein cannot leave the endoplasmic reticulum without folding properly, and thus it gets stuck and eventually gets broken down by the cell.
Calnexin (CNX) and calreticulin (CRT) bind to the glycan, and help the protein fold properly into its final form
The 11 year old boy and 6 year old girl have a mutated copy of the gene encoding for glycosidase I, called MOGS. Only one other case of this mutation has ever been reported, and in that scenario the baby died after 74 days. Without properly folding proteins, it is very difficult for cells to function effectively, and thus mutations in proteins involved in glycosylation are often fatal.
Antibodies are heavily glycosylated proteins. It makes sense that the siblings suffer from hypogammaglobulinemia, as their antibodies are not glycosylated properly and thus they are present in much fewer numbers.
So how does this mutation make the siblings highly resistant to viruses? Viruses have their own DNA (or RNA), and they create proteins from it by using the host cell machinery. In effect, the host cell reads the virus DNA and creates and processes viral proteins with the host’s proteins. These proteins must often be glycosylated.
Life cycle of HIV. The important thing to note is that the viral proteins are made and processed by the host
The virus uses the host glycosylation proteins in order to add the glycans it needs to the viral proteins. But for the siblings, who have a malfunctioning glycosidase I, virus proteins can not be folded properly and thus do not leave the endoplasmic reticulum to produce new viruses.
If they do leave, the viruses are malformed and do not operate as efficiently as they normally do (exactly like the siblings’ own proteins do, causing all of the disorders they possess). In fact, researchers found that when they exposed the siblings’ cells to HIV and H1N1 (two completely different viruses, both incredibly difficult to prevent and treat), the virus particles they retrieved were 50-80% less infectious. That means that the spread of the virus was reduced to less than half of what it was before.
Proof of this is present in their methodology. Viruses were able to enter the siblings’ cells no problem. It was after they had entered, and were trying to replicate, that the researchers found that something odd was going on.
This is a huge finding. The reason why vaccines and treatments for viruses are so difficult to produce, is because they often rely on attacking specific aspects of viruses. For example, vaccines rely on using the protein coat of viruses, by stimulating your immune system and allowing it to recognize the protein coat in the future. However, a lot of viruses change their protein coat over many generations (since viruses are so short lived, many generations can occur in a very short time and they evolve quickly, rendering vaccines and treatments useless).
Viruses almost universally must rely on the host’s glycosylation machinery in order to replicate because glycosylation is so complicated and involves many different enzymes. Attacking the hosts own glycosylation pathway would be a foolproof way of slowing down viral infections.
And it has already been proven that disruption of this pathway without killing the host is possible- the very existence of the siblings is proof of that. Of course, a treatment would only temporarily disrupt glycosylation. There are chemicals that do this, and with minimal side effects that are uncomfortable but not damaging.
Basically, there is a way to slow down viral infections, so that they are less than half as infectious as they were before. It should work on almost every virus in existence, and has been shown to work on both H1N1 and HIV. While it is not a cure, I think we can agree that making viral infections less than half as infectious, universally, is a pretty awesome discovery.
Sources:
Sadat M, Moir S et al. (2014). Glycosylation, Hypogammaglobulinemia, and Resistance to Viral Infections. New England Journal of Medicine, DOI: 10.1056/NEJMoa13028
Image of glycosylated protein retrieved from http://www.uic.edu/classes/bios/bios100/lectures/07_27_glycosylation-L.jpg
Image of phase 1 glycosylation retrieved from http://upload.wikimedia.org/wikipedia/commons/4/4b/N-glycan_precursor_synthesis_in_the_ER_lumen.png
Image of phase 2 glycosylation retrieved from http://www.zoology.ubc.ca/~berger/b200sample/unit_8_protein_processing/images_unit8/14_22.jpg
Image of calreticulin and calnexin retrieved from http://biowiki.ucdavis.edu/@api/deki/files/102/02_calnexincalret.gif?revision=1
Image of HIV life cycle retrieved from http://www.intechopen.com/source/html/16788/media/image3.jpeg
Surreal Science Stuff 
