A Vaccine Pathway for Herpes Virus with Gregory Smith, PhD

Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. It's estimated that more than half of people under the age of 50 around the world have a herpes virus infection, a lifelong condition with no cure. This infection can be much more serious than an occasional cold sore flare up. For some, it can cause blindness or life threatening encephalitis. They can also infect the nervous system, and there is increasing evidence that it contributes to dementia. Gregory Smith, professor of microbiology immunology at Feinberg, has been investigating a path to long needed vaccine development for the virus. He recently published findings in the journal Nature that bring the possibility of a preventive vaccine a step closer. Welcome to the show, Dr. Smith. 

Gregory Smith, PhD: Thanks, Erin. 

Erin Spain, MS: Well, you have been studying this virus for quite some time. Tell me about the various herpes viruses that exist in humans, the prevalence of these viruses and the work that's been taking place in your lab to really understand them. 

Gregory Smith, PhD: There are herpes viruses throughout nature that infect basically every mammal that walks this planet and humans. We have 8, traditionally, counting the first one recognizes herpes simplex virus type one, which we'll be talking about more today. But there's type two, there's Epstein-Barr virus, which causes mononucleosis. There's cytomegalovirus is Kaposi's sarcoma and then a few others. There's also sometimes a ninth that's referred to, which is actually a monkey herpes virus, but it can transmit from monkeys to humans, and it often causes a lethal infection. 

Erin Spain, MS: You mentioned a couple of different viruses, and this recent study published in Nature there was the herpes simplex virus type one and type two that you talk about. Tell me specifically about those two. 

Gregory Smith, PhD: So these viruses are actually quite closely related. So my colleagues actually said that if they were discovered today, they probably won't even get different numbers.  

Erin Spain, MS: Wow. 

Gregory Smith, PhD: So they're very close. But traditionally the way with most people think about these things in terms of what they do is they often will just colloquially say that type one causes infections above the belts and type two below the belts, so to speak. But the truth of the matter is these viruses are perfectly capable of infecting either site within our bodies. So you often think of type one causing cold sores around the mouth and type two with genital infections and sexually transmitted infection. But really, you can get type two, you know, in the face and mucosal layers of mount in the mouth and type one can get into the genitals. And in fact, in developed countries such as ours, HSV type one is more prevalent in the neurons that innervate the genitals than type two is. 

Erin Spain, MS: Tell me about the typical way that the virus infects and moves through the body. 

Gregory Smith, PhD: It starts off much like any other respiratory viral pathogen. So, like a common cold virus or influenza, you get exposed to it and it's going to start replicating in your mucosal linings. Typically in your mouth and your nose could also do your eyes anywhere that's exposed. And so in those tissues, the barrier, the cells that are exposed to the environment are typically an epithelial barrier cell lining, nucosal epithelial cells. And the virus is very tuned to entering these cells and replicating and producing much more virus. And as it does that, you know, if it's a common cold, you're going to start sneezing and wheezing and coughing and the viruses being produced will start releasing back out into your mucus. And basically, that's what's happening currently with the pandemic of coronaviruses as well. With herpes, there's something else going on. All of that is true here, too, but the important addition is that the virus can also transmit from those mucosal epitheial cells to deeper tissues and specifically to the nerve endings that innervate those tissues. So if you get punched in the face or in your lip and you feel that that hit, right? That's because there's a censoring our on our population sensory noise coming from a region of your peripheral nervous system called the trigeminal ganglion, which is a ball of neuronal tissue below your brain. It's not part of your brain. That's part of the peripheral nervous system, not the central nervous system, but nevertheless they have their nerve fibers protruding out to different parts of your face, including your lips. When you feel that's because there is a firing that action potential and that neuron that's conveying that sensory input all the way through those neurons of the trigeminal ganglion passing onto the brainstem in the brain. Ultimately, you consciously recognize you got hit and you go, ow!, OK. But the virus is actually using those nerves to actually physically move as opposed to an electrical impulse. It's using them to physically move within those nerve fibers, and we'll get to that trigeminal ganglia that I just described. And that's where it typically resides in us for the rest of our lives. 

Erin Spain, MS: Some people may be surprised to hear that the herpes virus can cause damage to the nervous system. Explain that damage to me. 

Gregory Smith, PhD: So in most cases, we presume that there isn't damage occurring. In fact, most people live with this virus may not even be aware that they're living with it, even though they might be shedding it, infecting other people. So, for the most part, doesn't seem like it causes much damage. So for anybody out there who gets cold sores, they shouldn't be worried that the sky is falling and bad things are going to happen to them. But there are cases where you do get clear damage in the most obvious one we talk about is herpes simplex encephalitis. That's probably about one in two hundred to three hundred thousand people who are infected. It's a really low number, but of course, it's very devastating when it does happen. So herpes simplex encephalitis is a disease, not only the virus killing cells of the brain, but also of your immune system doing destruction, trying to get rid of the virus. The really interesting thing here is that there was this kind of dogma in the field for a long time that the typical route of infection into the trigeminal ganglia and then the reactivation later in life that will bring it back out to your lip and maybe cause a cold sore that that's the norm. And then once in a while, bad things happen like encephalitis, but we realize it's not so black and white anymore. There is a range of disease that can manifest. And in fact, when people have done studies of cadavers that people die in car accidents or other things and looked at neural tissue from them, they found herpes simplex DNA matches and the trigeminal ganglia, but in the brain and then often in the brains of patients that didn't die because of herpes or something else. So the virus is going into lots of different kinds of neural tissue, much more than the dogma would have you believe. And one thing we should be thinking about is, well, what's the consequence of that? And what we're learning is that there might be some significant consequences, and there has been this suggestion that there could be associations with herpes virus infections of the nervous system, and instead of a full blown encephalitis that could kill you more subtle types of CNS disease that might lead to things like dementia or maybe even Alzheimer's disease. So this may not be the causative agent of those things, but it may be a contributing factor to these things. 

Erin Spain, MS: I want you to explain to me the main findings in this paper that you recently published in Nature. This was a really important paper. Tell me about that. 

Gregory Smith, PhD: The study was basically was getting at that central question: how does the virus invade our nervous system? There are a number of viruses that can infect the nervous system, but they are probably the minority viruses of human viruses that cause disease. Most human viruses infects the respiratory tract or the digestive tract. Very few get into the nervous system, but there's a number do. Classic ones are polio, which cause poliomyelitis, particularly in the 50s in the United States. And then there's rabies is another classic. When you get hit by a rabid animal, it's going to go right into your nervous system. Herpes is a little different, so herpes is what I would like to refer to as a proficient neuro invader, unlike those other viruses. It's going to get into your nervous system probably every single time that you get exposed. People could argue that rabies will do the same thing. It's true, but rabies is dependent on the animal to bite you and actually damage your tissue to get the virus into your nerves. Herpes doesn't even need that. So it's very good at being neuroinvasive and the mechanisms by which you can do that. No other virus is known to be able to get into our nervous system like herpes can so suddenly and easily. And so we really want to understand that molecular mechanism that underlies that phenotype to get a better grasp, not only how the virus is able to do that, but how we can ultimately use that information to stop it, or maybe even use that information to do other kinds of important research development, such as making new gene therapy vectors. Most viruses, not all, but most viruses use the microtubule side of skeletal tracks to get to where they need to go and ultimately replicate within that cell. And then for some viruses like herpes, that destination is the nucleus of the cell. Now the problem is that microtubules don't extend off the nucleus proper. They extend off another structure in the cell of something called a microtubule organizing center. And the most common form of that is called the central cell. If a virus is going to ride along a microtubule track and do it, so that's going inward bound the whole time doing a marathon run, so to speak. It's going to end up getting to the end of the microtubules, which are at the center cell, and then it's going to be kind of blocked from going any further. That's the end of the road. And it's also a kind of an interesting end of the road because a cell, for whatever reason, has evolved to have a lot of protein turnover, a lot of degradation occur at that side of the cell. So in a sense, the virus is running right into the trashcan of the cell, which is not a good thing. You would think for a virus to evolve to do. So, most viruses don't do that because probably because there's an inherent danger in doing that for the virus. So most viruses, what they do is again, a microtubule track and they just kind of bounce around. They'll go a little bit that way. They'll go a little bit this way. And basically, what they're ultimately doing is facilitating their diffusion within the viscous environment of the cell and given enough time, they'll get to wherever they need to go just by chance. OK, so you can call that a dumb virus. So herpes is on the marathon run, and so when it gets there, it's now in trouble because it can't just meander away from it. It's dedicated to going one direction and so it's going to get locked there. And so what we realize is there must be a second step that the viruses have evolved that once they get to the centrosome, that they must be able to leave the centrosome somehow then go to the nucleus, their final destination. And so the paper starts with this question of how does that happen? And there's been a hypothesis in the field that, well, once you get to the centrosome you would just have to use a different motor, like a different train engine that's moving on these microtubule tracks, a motor that belongs to the cell that the virus would then use to go to where it needs to go. It presumably would have to use a molecular motor called kinesin. And so we look for that. We ultimately did find that the viruses were hijacking the kinesin motor and using it to go from the cetersome to the nucleus, so it all kind of clicked into place. But then there was we got a big surprise as we continue to do this work that was completely unexpected to us, I think, to anybody. And that surprise was that when it does use that kinesin, the kinesin that's using is not from the cell that it's currently infecting. It turns out it's from a cell that infected beforehand from a previous round of infection. A more specific example is that the virus, when it's first replicating in our mucosal epithelia, those exposed tissues in a respiratory tract, it's actually picking up kinesis in those epithelial cells. I had a colleague tell me, Oh, so herpes viruses are taking this as a putting it in their backpack and they're going to pull it out later and saving it for later. And that's I think I think that's a great analogy. So now here's the new scenario. The virus is doing the marathon run down a nerve fiber on its way to the trigeminal ganglia. Eight hours later, it gets to the centrosomes and then it reaches into its backpack and it pulls out that kinesin that it stole from the epithelial cell long ago and now it uses that specifically to go from the centersome to the nucleus. And so not only was this explaining an aspect of how these viruses so efficiently get into our nervous system, but it was the first demonstration in all of virology that I'm aware of, and I've talked to a lot of people about this, where a virus grabs a cellular protein and makes it part of the viral particle so that that protein now becomes a pro-viral, that is something that supports infection, a pro-viral component of the viral particle for subsequent rounds of infection. Since that had never been seen before, we wanted to come up with a name for this process, and we referred to it as assimilation. So basically, the kinesin has been assimilated by the virus, and for any Star Trek nerds out there, I will admit that part of the reason that name came up was thinking of the captain of the Enterprise that gets captured by the Borg, and he's assimilated by the Borg and becomes one of them is now fighting with the Borg instead of with us, with the Enterprise. And that's kind of how we think of what's happening here with kinesin. 

Erin Spain, MS: So interesting and you said that you've been talking to colleagues about this finding and they're all just as surprised as you are. 

Gregory Smith, PhD: Oh, yeah, yeah, everybody's very surprised by this because there was no precedent. There was a precedent that viruses capture cellular proteins into their viral particles that release from cells. That had been seen for quite a while. And in some cases, viral proteins can actually be antiviral. So there's this classic group of proteins called APOBECs. They're very well-studied studied in the field of HIV, where they actually can hinder the ability of the virus to infect the cell. So they kind of have of torpedoes that go as the viruses are leaving the cell, they go in and they plant this little bomb into the virions so that when the virions try to infect another cell, they can't do it anymore. They get disrupted by it. So it's a clever antiviral mechanism of the cell. There are also lots of other proteins are known to be put into viral particles just in general, but for no apparent reason that maybe they're just kind of gobbled up by random chance. But this is an example where evolutionarily the virus has adapted to take a protein and use it later on, and that's the first time. 

Erin Spain, MS: Well, how does this open doors to a possible vaccine? 

Gregory Smith, PhD: We now have a way to make a new type of live attenuated vaccine by removing the ability of the virus to invade the nervous system, you’ve now attenuated its ability to not only be neuro-invasive but to cause lifelong latent infections. And because most of the diseases that can happen, including cold sores and encephalitis. So now you have a virus that you can put theory into the mucosa. I sometimes imagine, just like having a chapstick formulation, you just rub it on your lip. No needle involved, right? No adjuvant. You just let the virus do its thing. But herpes is evolved to run and hide in your nervous system and get you for life. These particular attenuated viruses can't do that if you mutate what we've learned is the virus is doing. The immune system sees us very robust infection in your mucosa, in your respiratory tissue, and it goes after a full force saying, "Oh my gosh, we got to do something here." And after it clears it because it's going to win because the virus can't hide anymore, it's going to have the most adapted, ready to go immune response possible when you get exposed to the real thing later in your life. And so we think this is going to be the key discovery that's going to allow for vaccines to be successful for the first time. 

Erin Spain, MS: What's the next step? What happens now, you've published this paper, you have this discovery. When could we possibly see vaccine trials based on these findings? 

Gregory Smith, PhD: And so we're working effortlessly to get this technology for it. And outside of my academic lab, in collaboration with Northwestern, a startup company was formed. It's called Thyreos, Inc. So the company is working to make these vaccines a reality. And what's kind of interesting about this is these fundamental properties of how these herpes viruses into the nervous system are not unique to herpes simplex virus type one or type two, it's fundamental to all the neuroinvasive herpes viruses, whether it be those, whether it be chickenpox virus, varicella zoster virus, whether it be a veterinary pathogen of your cat at home or the cattle from which we get the beef, for the food industry. All of these have neuroinvasive herpes viruses are causing severe disease in those animals and all of those viruses can be designed to become libertine viruses that can be the nervous system using technology that we've been able to develop. So we're hoping to make a whole bunch of vaccines here based on this basic idea and furthermore demonstrate feasibility between all of them. So if we show that a pig vaccine works the way we does and we stand and we show a cow one that does, that just further reinforces that this is a good, solid approach for going after human ones. But we're not waiting. We're going after the human ones right away to all in parallel.

Erin Spain, MS: What about folks who already have the virus? 

Gregory Smith, PhD: So this is a question that I get a lot. You know, I often will get emails from individuals, too. Asking about this said that are outside of the scientific community. The idea of having vaccines that are prophylactic, which is what we ultimately want to be able to develop ones that will prevent you from getting infected. So these would be ones given probably as an adolescent vaccine. These same vaccines could be used as therapeutics. Just like right now, we have therapeutic vaccines for varicella zoster virus and shingles. Right? So the hope would be that a person who has this a high recurrence, HSV infections is suffering from this, more so than the average person that you could give them the vaccine as a way to boost up their immunity and help suppress their infection. So it's a treatment. It's not a cure, but it could make a world of difference. 

Erin Spain, MS: Is there anything else you want to add or that you just want to sum up for us today? 

Gregory Smith, PhD: You know, studying herpes simplex viruses, I've been doing this now for 20 years in Northwestern and five years before that at Princeton as a postdoc. It's been a real eye-opener. You really get a sense of what pathogens are able to accomplish, and they're just so fascinating. If I could do it all over again, I'd probably just do the exact same thing that I did, because every time we discover something the virus is doing, it just blows our minds. And this last publication was probably one of the more exciting things that we've ever discovered. But it's just one in many of these viruses just teaching us about biology, and it's just an exciting thing to be studying. 

Erin Spain, MS: Thanks so much for listening. Please subscribe to Breakthroughs on Apple Podcasts or wherever you listen to shows. And if you are a medical professional, you can claim CME credit just for listening to this episode. Go to our website feinberg.northwestern.edu and search Breakthroughs CME.