Going Viral for the New Year

About half of the population, unfortunately me included, is infected with the harmless but pesky herpes simplex virus type 1, HSV1. The occasional cold sore is annoying (think blunt needle trying to poke its way out of your skin), but I can't help admire the apparent ingenuity of the viruses that, quite literally, live inside my head.

That viruses are so small makes their often-sophisticated lifecycles even more remarkable. The relationship between HSV1 and its host is lifelong (like family!) and begins with infection of the epithelium, often cells on the skin or mucous membranes of the face. It's in these cells that the viruses can replicate and infect new, unsuspecting hosts by direct contact.

Though HSV1 persists in the body, outbreaks are infrequent. The virus remains latent in neurons of the peripheral nervous system, biding its time between outbreaks. The peripheral nervous system is the network of neurons that carry information to and from the brain and spinal cord that together make up the central nervous system. The peripheral nervous system is not protected by the blood-brain barrier and is therefore more vulnerable to infection.

When stress or illness trigger HSV1 to exit latency, the virus heads back to the epithelium, where it can try to infect new hosts.

Entering and exiting the cell bodies of peripheral nervous system neurons requires transport of the viruses up and down axons, the long cables that transmit electrical pulses to the synapse. The viruses do not float around randomly. It would take far too long to crawl the length of an axon by chance. Instead, the viruses hijack motor proteins, which cells use to transport a variety of cargo along microtubules, the protein highways used for long-distance transport.

Microtubules are long chains of tubulin proteins. Because tubulins are not symmetrical, microtubules are polarized. One end is different from the other. Neurons take particular care that microtubules heading down their axons are uniformly oriented, with the so-called plus ends near the synapses and the minus ends near the nucleus.

During initial infection, viruses need to move into the cell body by climbing up an axon from the synapse. To move in this direction, the virus recruits dynein proteins (see the image), which move along microtubules toward the nucleus. Dynein motors attach themselves to cargo on one end, and hobble along microtubules with two legs on the other end.

During an outbreak, HSV1 has to move in the opposite direction, away from the cell body down axons directed toward the skin. Dynein motors only move toward the nucleus, and so instead the virus hails kinesin proteins, functionally similar but quite different in structure. Besides moving in the opposite direction, kinesins are composed of different protein units and move in a proper stride, one foot ahead of the other.

These little walking proteins, dynein and kinesin, carry all sorts of cargo around cells, even mitochondria. Higher organisms have multiple variations of each type, with specialized versions for particular cell types and cargos.

Here's to my kinesins: may they only transport my own, human proteins for the foreseeable future.

Image credits: Enquist et al. (2012), their Fig. 1 (CC-BY license); PDB ID 3VKH, rendered with Jmol

References:

Enquist, L. W. Five Questions about Viral Trafficking in Neurons. PLOS Pathogens 8, e1002472 (2012). [Open Access]

Kramer, T. & Enquist, L. W. Directional Spread of Alphaherpesviruses in the Nervous System. Viruses 5, 678-707 (2013). [Open Access]

For more on kinesins, see the Structural View of Biology page here.