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Unlike with many other viruses, once you get a herpesvirus you’re stuck with it for life. But just how do these master trespassers accomplish this feat?

Hosted by: Hank Green

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[♪ INTRO].

Getting sick is never pleasant, but at least many viral infections are one-and-done. We've talked before about how the measles virus is the poster child for lifelong immunity.

Once your immune system recognizes it, it never forgets, and it will not hesitate to kick it to the curb if it shows its face again. Unfortunately, however, there's also a poster child for lifelong infection: herpesviruses. These viruses are so good at sneaking past our immune system and hiding out in our cells that once we have ‘em, we… have ‘em.

Because herpesviruses have some unique features that make them master squatters. Which seems kind of embarrassing for our immune systems — but actually, we may have evolved to coexist. There are eight members of the herpesvirus family that routinely infect humans.

These include herpes simplex virus 1 and 2, which cause oral and genital herpes, as well as the viruses that cause chickenpox and shingles, and most — but not all — cases of mononucleosis, or mono. Herpesviruses are nearly everywhere. It's thought that more people on this planet are infected with herpes simplex 1 than not.

Herpesviruses are known for being unusually large and complex, as viruses go. Their genomes are so large, with so many different genes, that they can make dozens or even hundreds of proteins. That's way more than other viruses — influenza virus genomes, for instance, only make twelve proteins.

These proteins give herpes all kinds of tools that let it infect a host...forever. Like a gang of thieves in a heist flick, these viruses slip past all of the traps and defenses our body puts out for them, one by one. First, herpesviruses have to get past our innate immune system — the part of our immune system that holds off new, unknown invaders — without being noticed.

It's a sneaky move known as immune evasion. The innate immune system's first line of defense against new threats starts with the production of proteins that kick cells into bouncer mode, setting off a huge signal cascade that ultimately prevents viruses from using host cells to replicate. But herpesviruses reduce the cell's production of those bouncer proteins, which dampens cells' first line of defense.

But cells have backup defenses against viruses that can get past this pathway. Which herpes also has an answer to. Herpesviruses can integrate themselves into the host's DNA, which can cause damage to host's genome.

And cells are normally super vigilant about monitoring for DNA damage. But herpes can convince them to overlook it. For example, herpes simplex virus 1 produces proteins that basically sabotage the cell's DNA damage warning and repair machinery and take it over.

The next trap seems inescapable: When all else fails, a cell making a last-ditch effort to contain a virus will basically kill itself. But you probably know where we're going with this by now. Herpes has proteins that can evade the cell's self-destruct signals.

Once it gets past the innate immune system, herpes has to stay out of trouble long enough to set up camp within the host's cells. While it's working on that, herpes is in what virologists call the lytic phase — it's actively reproducing and sending out new viruses. And that gives the body's adaptive immune system — the one that develops antibodies that can bind to viral molecules, or antigens — a chance to recognize those viral particles.

But herpes puts the brakes on this process, too. Normally, there are specialized cells that grab bits of viral antigens and show them to the immune system, like molecular snitches. But herpes gums up the cellular machinery that would normally move antigens into position for the immune system to recognize it.

Still, the host does eventually develop antibodies. Only by this time, it is too late. The antibodies can't clear the infection because herpesvirus is already hunkered down inside the host's cells.

This is called the latent phase. The virus packs up its genome in a tight, circular form, and only certain parts of it continue to be expressed. For this to work, the cell it's using as a secret hideaway has to stay alive.

So the viruses typically target types of cells that last a long time and perform critical functions, like neurons and immune cells. The body is a lot less likely to sacrifice those just to kill off a virus. Then, herpes basically hangs out.

Forever. Or at least, until the virus determines that it's safe to re-enter the lytic phase and reproduce -- at which point, congratulations on your new cold sore. But it turns out, in a lot of people, herpes may be… more of a frenemy than an outright foe.

Herpesviruses certainly cause their fair share of problems. The infections can be severe for immunocompromised people, and they're a leading cause of blindness worldwide. They can also cause some cancers.

But for the most part, herpesviruses have evolved to keep their hosts alive and healthy enough to interact with others and infect new hosts. Chickenpox blisters and cold sores are the exception — many herpesvirus infections are mild or totally asymptomatic. Like, by the time we hit 35 years old, most of us have been infected with the herpesvirus known as Epstein-Barr.

And most of those who are infected have no idea. That's right: EBV causes most cases of mono, but that miserable sore throat and fatigue doesn't happen to most people who get it. Lucky them.

And weirdly, having herpes hanging out might actually benefit our immune systems. But that's a story for another episode. In the meantime, if you had chickenpox as a youngster, at least now you know: you had the privilege of hosting one of the most talented viruses around.

Thank you for watching this episode of SciShow. Much like a herpesvirus infection, our patrons stick with us through thick and thin. You're always there for us, and you come out in even more strength when things get bad.

You help us make videos for everybody, even those who cannot pay for them. We love you, even though we just compared you to herpes. If you want to get involved and help support what we do here, check out [♪ OUTRO].