Latency, Long Covid, and the Dreaded Rererebound
If a virus has the ability to quietly hide, you have to revise your battleplans
Yesterday’s post, “Bullfighting Covid,” explores the idea that SARS-CoV-2 is waving a metaphorical red cape that tricks the immune system into thinking it’s fighting worms instead of mounting a more effective antiviral Th1 response. Fortunately for me, vaccination gave me a standing army of properly trained antiviral Th1 cells armed to destroy cells expressing SARS-CoV-2 Spike protein. Although my pre-existing anti-Spike response quickly brought my sinus-localized Covid infection under control, it evidently didn’t fully eradicate the infection because it came back in two separate rebounds over the course of three weeks. The simplest explanation for the rebounds is that SARS-CoV-2 uses a crafty virological trick called latency.
HIV is a familiar story illustrating the principle of latency. Combination antiretroviral therapy can effectively reduce the amount of HIV in a person’s blood to near zero, which effectively reduces the person’s risk of losing all their helper T cells and progressing to AIDS to near zero. Unfortunately, HIV is able to temporarily shut off all of its genes and enter a quiet sleeping state in the long-term safehouses provided by resting memory T cells. We haven’t yet come up with a way to eradicate HIV from the resting memory T cell reservoir, so if a person stops taking antiretrovirals then HIV will eventually re-emerge from hiding to rekindle an active infection and resume the inexorable progression toward AIDS1.
In another example, the fact that human papillomaviruses (HPVs) can establish a latent reservoir is why the HPV vaccine only works to prevent infection and can’t eradicate established infections2. The HPV coat protein the vaccine targets isn’t expressed in latently infected cells.
My emerging model is that SARS-CoV-2 has an active state, in which lots of Spike is expressed, and a latent state, where the virus doesn’t express any Spike. I imagine that my anti-Spike T cells repeatedly came in to eradicate all the actively infected cells in my sinuses but the Spike-directed immune response had no way of detecting cells harboring sleeping latent viruses. After my T cells finished cleaning up the Spike mess the immune response went back to a resting standby state. Then a week later the latent SARS-CoV-2 rekindled into an active Spike-expressing rebound infection, rinse lather, repeat.
Latency is classically a trick of viruses whose genomes are made of DNA, so it’s important to note that the SARS-CoV-2 genome is made of RNA - which is a lot less stable than the DNA genomes of latent HIV or HPV. It’s good news. While HIV and HPV can trick the cell into replicating the viral DNA, the cell doesn’t have any mechanisms for replicating RNA. RNA replication is strictly a viral thing. It means that persistent SARS-CoV-2 latency would likely depend on at least occasional expression of the viral “early” genes that maintain the viral RNA by occasionally replicating it at low levels. That means there’s an opportunity for killer T cells or antiviral drugs to find the viral early genes and destroy the latent virus3. It’s a much less challenging form of latency than HIV or HPV.
During my Covid infection, it apparently took my immune system multiple rebounds before I was able to mount an effective response against the early genes expressed in latently infected cells. This was presumably because of Covid’s red capes of histamine flummoxing. An n=1 experiment tells us nothing, but I note that I didn’t catch up with the idea of taking azelastine until the beginning of my second rebound. Assuming I don’t have a third rebound, I might guess that taking an antihistamine had something to do with my immune system finally waking up and smelling the early gene coffee.
In the longer run, an obvious way to attack the latency problem would be to incorporate one or more SARS-CoV-2 early genes into Covid vaccines. That way we’d theoretically be able to pre-train a standing army of Th1 cells in the absence of the red capes of a full-blown SARS-CoV-2 infection. A hitch is that nearly all the SARS-CoV-2 early proteins are known to have immune-flummoxing activities - and there are presumably plenty more flummoxing activities remaining to be discovered. My favorite early gene target is a protein called papain-like protease (NSP3). I like NSP3 because all its known flummoxing functions are exerted through its ability to chew up other proteins - and I know exactly how to inactivate NSP3’s protein-chewing activity with a single mutation. The sequence of NSP3 is highly conserved - meaning similar NSP3 sequences are found in distantly related coronaviruses. An NSP3-containing vaccine might also be a cure for common cold coronaviruses?
Latency can also explain how SARS-CoV-2 manages to persist in the gut and brain for years, particularly among long Covid patients. Although persistently infected tissues show scattered cells expressing Spike, the latency model predicts the Spike-expressing cells are just the tip of tha much larger iceberg. In other words, alongside the Spike-expressing cells there may be many more cells expressing just enough SARS-CoV-2 early genes to occasionally replicate the viral genome. In addition to preventing rebounds, an NSP3-containing vaccine might conceivably alleviate long Covid?
I’m putting the finishing touches on an upcoming post, “Covid Just Messed with the Wrong Team,” in which I’ll dream big about the idea that a coming age of faster/cheaper vaccine approaches could make it easier for us to experimentally test the predictions of latency hypothesis. And also save the world4.
I can’t resist throwing in a weird hypothesis I’ve been idly speculating about since grad school. Latent HIV sleeping in a resting memory T cell probably doesn’t express any viral genes - so it doesn’t have any unique targets for drugs or the immune system to go after. However, if the memory T cell wakes up from its resting state to undergo cell division, it’s likely that the process of replicating the cellular DNA will temporarily awaken the latent HIV to express at least a little and its Tat and Rev early genes. If you gave somebody an mRNA vaccine that elicited killer T cells targeting Tat and Rev, the latently infected cells might be killed - but the problem is resting memory T cells can go for many years without dividing. The immune system has feedback loops that maintain different classes of cells at roughly the same level, so the idea is that an HIV-positive person on effective antiretroviral therapy could get a Tat/Rev vaccine and then periodically undergo a process called leukapheresis, which removes white blood cells from circulation. Resting memory T cells would then have to divide to replace their lost neighbors. Each round of leukapheresis only removes about 1% of the body’s T cells, so you’d have to do it weekly for a couple years before the numbers would start to add up. Testing the prediction that HIV might be cured this way would be very expensive, but if the principle could be proven then the field could work to see whether there are cheaper ways to do it. Curing people of HIV sure would be nice.
Although the HPV vaccine can’t eradicate an existing infection, it remains possible that the vaccination could stop the infection from spreading to new sites (see: “We Tuskegeed My Dad”).
For complicated reasons, the word “destroy” may be wishful thinking here. Effective antiviral Th1 responses are generally armed with a potent weapon called interferon. A foundational bit of thinking from Skip Virgin invokes the principle that viruses with latency mechanisms are often tuned to detect interferon signaling, such that the virus can respond by voluntarily going to sleep if it looks like there’s a firestorm of Th1 activity in the environment around the infected cell. It’s possible rebounds could be controlled by the presence of Th1 cells that simply come in and secrete a little interferon, which might effectively put the virus to sleep. That’s very different from my dream scenario in which a killer T cell targeting SARS-CoV-2 early genes destroys the infected cell. It remains grimly conceivable that SARS-CoV-2 will be quietly sleeping in my sinuses for years to come.
Song of the day: “So You’d Like to Save the World” by Lloyd Cole.