Viruses at the crossroads of infection

Last week I wrote about a recent paper showing that in some cases influenza viruses can escape from the lungs of an infected person; here, it makes it's way to the local lymph nodes by infecting your lung's sentinal immune cells, the dendritic cells. In this instance, this mechanism is probably being used by our own body's as a defence: by capturing influenza virus in the lung we can kick start our immune system by handing it directly to T and B cells within the lymph nodes. But it can also have deadly implication, especially considering that possibly every virus will have some run in with a dendritic cell during an infection.

**for a great discussion of what goes on inside lymph nodes during the induction of an immune response, see last weeks This Week in Virology**

Complicated diagram of the role of dendritic cells in the immune response. On the left, DC's grab antigen (for example a virus) and thus move into nearby lymph nodes. Here they present antigen to T cells ( or B cells). These cells leave the lymph nodes to hunt down their specific antigenic target (shown on the right here whether the T cells move into infected tissues. What DC's can also do is carry infectious viruses into the lymph nodes where they are free to replicate inside the dense population of T and B cells. http://www.biken.osaka-u.ac.jp/COE/eng/project/images/fig-hirata-jpg.jpg

 Your dendritic cells (and all other antigen presenting cells) allow this by sucking up lots of virus particles and digesting them inside their cytoplasm. The viral proteins are chopped up into smaller chunks and are transported to the surface of the cell (see the MHC pathway); here they are in a great position to encounter B and T cells - mostly in the lymph nodes - whereby they interact with the likes of the T cell receptor molecule and cause the massive increase in virus-specific adaptive immunity (lots of T cells and lots of antibody producing B cells that will eventually cure you of your infection). See the above diagram.

But in some viral infections, the virus manipulates this natural behaviour of dendritic cells to spread throughout the body and establish a systemic infection. This is what measles and HIV do, and this is why they can be so dangerous.

During an infection a virus now has two choices (or your body enforces these decisions) : it can either a) be degraded and presented to cells in the lymph node (MHC pathway via antigen presenting cells), or B) avoid degradation and physically infect and replicate in those T and B cells (what measles and HIV do). This is an incredibly important cross-roads during an infection as it may lead to a fully functioning immune response to defend against the pathogen or it could lead to a potentially life-threatening illness. So, what controls this choice? Especially considering that it will be a complex process governed by a balance between virus manipulation and host defence; the main question is where does the balance lie?

HIV particle - the molecules accessible to the immune system are: gp120, 41 and the lipid membrane. Research shows that the sugar coating of gp120 (Env) may allow the virus to escape degradation and infect cells within lymp nodes. Wikipedia.

A paper out recently, in Journal of Immunology puts forward the idea that it is the sugar coating of a virus that may determine whether it is degraded or can go on to infect other cells. Using two versions of HIV (one with 'natural' sugars and the other enriched with another kind) the Dutch group show that the viruses differed dramatically in their ability to be degraded or be transmitted following interactions with dendritic cells at exactly the important cross roads.

HIV Env protein on its surface is covered in sugar molecules which can be recognised by human lectin (sugar-binding) proteins on the surface of dendritic cells. These allow the virus to be ingested and presented to T and B cells. Other sugars, however, allow the virus to escape this potentially by reducing binding.

Viruses are not just simple groups of protein and nucleic acids wrapped in a bag of fatty lipids; they are also decorated with abundant sugar molecules. These sugars are added to viral proteins (making them 'glyco' proteins) during replication inside a cell. This modification alters the biochemical behavior of their proteins, which allows them to evade antibody binding (a glycan shield), for example. This is especially true for the HIV glycoprotein: Env, (also known as gp120) found on the surface of the virus particles. Your body knows this and has evolved to deal with it by developing sugar-specific binding proteins that are found on your dendritic cells: one example is DC-SIGN, a sugar-binding lectin protein. Other proteins are used for other viruses. But what this research shows is that the war between pathogen and host is being fought on the battlefield of sugars found on Env: one sort allows the virus to continue infection while the other forces it be degraded. Binding to these cell surface proteins may also modulate the virus's ability to leave infected cells: increased binding will lead to reduced transmission. It is clearly a balanced process between binding initially (virus wants to get near these cells), not binding too much (virus doesn't want to be degraded) and binding enough so as not to be hindered when leaving.

The next step in this field will be in identifying the roles of specific sugar modifications in deciding the fate of the virus.  Also we should investigate the mechanism by which the virus overcomes the built-in degradation pathway in dendritic cells and the ways in which our cells use the sugar molecules to recognise virus. If all viruses encounter these cells (they are found in every tissue), how then do some infect the cells while others are mainly ingested? How can we use this to our advantage through forcing viruses down one pathway instead of the other in the hope of eliciting a stronger immune response?

van Montfort T, Eggink D, Boot M, Tuen M, Hioe CE, Berkhout B, & Sanders RW (2011). HIV-1 N-glycan composition governs a balance between dendritic cell-mediated viral transmission and antigen presentation. Journal of immunology (Baltimore, Md. : 1950), 187 (9), 4676-85 PMID: 21957147