Hiding in Plain Sight: How cytomegalovirus evades the immune system

Lately, it seems like every time you turn on the television or look at a news app, every other story is about a virus. In particular: SARS-CoV-2, which causes COVID-19. Yes, viruses are certainly hogging the headlines these days. But even with so much focus on the deadly COVID-19, some of the less-threatening viruses are still present and doing damage, even if you don’t know their names. 

Even before COVID-19, you may have never heard of cytomegalovirus, otherwise known as CMV. And it would like to keep it that way. 

Meet cytomegalovirus 

While some infectious agents kick up a big fuss when they infect you, causing your body to go wild trying to stop it and making you feel gross, CMV is a stealthy virus. It would prefer to carry out its plans under the radar, using your resources, and never being detected by your immune system. 

CMV is a member of the herpesvirus family. You may have heard of one of CMV’s cousins, herpes simplex virus, which causes cold sores. Like herpes simplex virus, once CMV infects your body, you will be infected for the rest of your life. It doesn’t cause any symptoms in healthy people, but people with poor immune systems can become very ill. CMV can also be transmitted from a healthy mother to an unborn baby, causing an illness in the baby. 

Scientists want to understand how CMV manages to evade the immune system so well, so they can design ways to fight it. A new study out of Germany recently found that CMV doesn’t just hide from our immune system, it actively sabotages it. The researchers studied two viral proteins that CMV makes and uses to subvert the immune system’s defenses and destroy the tools we use to eradicate it. 

Viruses versus the immune system

Viruses are not free-living entities like bacteria; they must enter our cells and co-opt our resources in order to propagate. They infect cells, build more of themselves using the cell’s equipment, and then spread to the next cell. To stop the virus from infecting cell after cell, the immune system has to find and destroy all virus-infected cells. One of the main tools it uses to identify infected cells are antibodies. Antibodies are proteins the immune system makes to recognize infectious agents and mark them for destruction. Antibodies can recognize and bind to viral proteins that CMV expresses on the surface of our cells as part of its reproductive cycle. When antibodies bind these viral proteins on the surfaces of cells, they form immune complexes which act as flags to the immune system, signaling that that cell needs to be destroyed. Natural Killer cells are immune cells whose job is to circulate through the body, looking for infected cells. When they see immune complexes on the surface of a cell, they know it’s infected and proceed to bind to the immune complex and release substances that kill the cell (Figure 1). This process is called antibody-dependent cellular cytotoxicity (“cyto” means cell, and “toxicity” means killing). Fortunately for CMV, it has evolved some brilliant counter-defenses. 

Figure 1: Antibody-dependent cellular cytotoxicity. Natural killer cells use a receptor protein on their surface to recognize virus-infected cells. This recognition occurs when the NK receptor binds to an immune complex, or an antibody attached to a viral protein. Recognition of the immune complex by the NK cells leads to death of the virus-infected cell, thereby stemming the flow of viral spread. Created with BioRender.com.

CMV makes two proteins, called gp34 and gp68 which work together to help CMV-infected cells remain unmolested by natural killer cells, allowing CMV to continue propagating itself. Both gp34 and gp68 are expressed on the surface of infected cells, and both have the ability to bind to the antibodies that form immune complexes on cell surfaces. gp68 binds to the same location that a natural killer cell would recognize and bind to, taking up that space and preventing NK cells from binding, making it very useful on its own to keep the CMV-infected cell alive. gp34 binds closer to where the antibody is attached to the cell surface viral proteins it recognized (Figure 2). 

Working together

All proteins, when they are made in the cell, contain certain “tags” that direct where they will go in the cell, whether to an organelle (a location inside the cell, like a room inside a house), or onto the surface. gp68, it turns out, has a tag that sends it to the lysosome. Lysosomes are organelles filled with digestive chemicals that destroy proteins. 

The scientists showed that when gp34 binds to the antibodies of immune complexes, it pulls them, and the viral proteins bound to them, inside of the cell.  With the help of the lysosomal tag on gp68, it can then drag the immune complexes and viral proteins to lysosomes where they are destroyed. Without the immune complexes on cell surfaces, natural killer cells won’t be able to recognize infected cells and therefore can’t destroy them (Figure 2).

Figure 2: CMV-mediated evasion of NK cell killing. CMV produces two proteins, gp68 and gp34, that travel to the surface of infected cells. There, these proteins bind to immune complexes, preventing NK cell recognition of the infected cell by 1) obstructing the binding site of the NK cell receptor and 2) dragging the entire immune complex into the cell. In this way, CMV prevents NK cells from recognizing that it has infected a cell, thereby protecting it’s host cell from death and preserving its own life cycle. Created with BioRender.com.

Interestingly, neither gp34 or gp68 is able to perform its function well on its own. It takes the expression of both proteins to effectively inhibit antibody-dependent cellular cytotoxicity. In this way, these proteins work as a one-two punch to knock out immune complexes and keep CMV flying under the immune system’s radar. 

Why it matters

Knowing how CMV uses gp34 and gp68 together to evade the immune system means that scientists will be better equipped to design antiviral drugs that can target these proteins. After all, knowing your enemy is part of the art of war. 

While CMV may not be very newsworthy, it can cause terrible disease in immunocompromised people, such as people needing to take drugs to suppress their immune system after receiving an organ transplant. And following the model of these scientists, hopefully more questions will be answered as to how other viruses escape the notice of the immune system.

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