Zombie Viruses That Come Back From the Dead

Halloween is a time for supernatural imaginary creatures, like zombies. But real organisms, such as viruses, can also come back from the dead! This blog discusses viruses that like a zombie return once you think they have been defeated. 

When we imagine being infected by a virus, getting a cold, for instance, we’re typically thinking about the ‘productive phase’ of infection. This is where new viruses are released from cells after the parent virus has hijacked the cell and its genome has been copied.  

However, a few human viruses behave more like the infamous brain-eaters of fiction. These viruses can lie dormant within the cell, only to reactivate again, allowing the virus to replicate itself and spread.

Other viruses, such as hepatitis B, can be even sneakier. Like zombies in a deserted graveyard, they can linger as a persistent infection, replicating slowly at low levels in the body without doing too much damage to the host cells (Traylen et al. 2011).

Undeath Toll

Some reactivating viruses are merely annoying. One example is the herpes simplex virus (HSV)-1, which most people are familiar with as causing recurrent cold sores.

When we get a cold sore, the theory goes that our localized immunity is compromised, allowing our existing herpes simplex infection to spread and cause tingling, a burning sensation, and then fluid-filled sores (Margolis et al 2007).

Other viruses, however, do significantly more damage. Hepatitis B, for example, is an inflammatory disease of the liver that chronically infects an estimated 257 million people worldwide (Smalls et al 2019).

Over a lifetime, 15-40% of people with persistent hepatitis B infection will develop liver failure, cirrhosis of the liver, or liver cancer (Fattovich et al. 2008). That’s equivalent to 900,000 deaths every year (Meng et al. 2020) — more than even the most blood-soaked zombie movie!

People facing the greatest risk of hepatitis B reactivation are those taking immunosuppressants, like adalimumab for psoriasis or undergoing chemotherapy for cancer. Patients starting these treatments in the USA are often screened for the hepatitis B virus (Smalls et al. 2019).

Antiviral Baseball Bats

Zombie infestations in the movies are often tackled by hitting them with baseball bats. In the real world, chronic hepatitis B infection is treated with antivirals, such as pegylated interferon (Ye and Chen 2021) and nucleoside analogs, like adefovir (Smalls DJ et al. 2019).

Adefovir works by inhibiting the ability of the hepatitis B virus to use reverse transcriptase to copy its RNA into the DNA of the host cell —where it’s (accidentally) replicated to produce new viruses (Baker 2005).

Patients taking high-dose immunosuppressants or chemotherapies in the USA are often offered prophylactic antivirals (Smalls DJ et al. 2019). Their response to interferon-based therapies may vary depending on the variant of the hepatitis B virus, which depends— in turn — on the part of the world it’s found (Lin and Kao 2015).

Towards a Cure for Zombies

Just like an American teen with a baseball bat, however, these treatments don’t cure the zombie outbreak — they just reduce the number of new zombies being produced. Most patients need to take nucleoside analogs for long periods to avoid a flare of liver inflammation.

Interferon-based therapies can suppress viral replication entirely, but the host cells still retain mini-chromosomes, called covalently closed circular DNA (Zhao et al. 2020). These ccDNAs allow the hepatitis B virus to return, again, from the undead if the patient’s immune system becomes deeply damaged.

For this reason, researchers are now investigating whether they can achieve the holy grail of every zombie movie — a way to eradicate the ccDNAs that cause the undead virus to rise. They are looking to use patients’ own immune systems to fight the virus (Meng et al. 2020).

But how do we know this will work? Among the clues is a study that found that some hepatitis B infections could be cleared following bone marrow transplantation (Lau et al. 1997). Scientists have found that, in chronic hepatitis B infection, the immune response becomes dysfunctional.

T cells that specifically target the hepatitis B virus may become exhausted, for example, due to inflammatory damage to the liver.

More than 50 clinical trials have been performed on vaccines to boost patients’ immune response to the hepatitis B virus. These may use DNA to encode the surface antigen on the hepatitis B virus, and to present these to B- and T-cells to provoke an immune response.

Other strategies for curing hepatitis B rely on the emerging class of cell therapies. These powerful treatments use genetic engineering to restore the function of exhausted CD8⁺  T cells, which target the hepatitis B virus.

Although many of these treatments have been tested in animals, only a few have reached clinical trials in humans so far — and with varying degrees of success (Meng et al. 2019). But, as with every good zombie movie, it’s just a matter of time before a plucky scientist formulates a cure for the outbreak and saves the day!