#29 – Cytomegalovirus: the Quiet Lifelong Passenger

00:00:05: The problem is, as I mentioned earlier, immunocompromised patients.

00:00:09: Here specifically also work and transplant patients but also individuals living with HIV especially if they have a weakened immune system that has progressed towards AIDS.

00:00:47: Low and welcome to this episode of Birological!

00:00:50: This was recorded on August the twenty-fourth in New York.

00:00:58: Today we are going to talk about the herpes virus again.

00:01:01: And this time it's gonna be the human cytomeclovirus or CMV, or H-CMV H for Human.

00:01:11: Yeah!

00:01:11: This is a herpes Virus.

00:01:13: It also called Human Herpes Virus V and it has alot of relatives in animal kingdom The closest relatives sitting in monkeys & apes Chimpanzee, CMV for example Rhesus CMV.

00:01:27: But there's also CMV or cytomegaloviruses in mice, for example.

00:01:34: So that is a lot of them around and CMVs are related to other herpes viruses like Epstein-Barr virus or herpes simplexvirus but they're little bit further away.

00:01:46: Like all herpesviruses these viruses have large DNA genome thats linear and double stranded.

00:01:54: For human cytomegalovirus, it's about two hundred thirty-five thousand base birth long.

00:02:00: So that is a lot of letters and this genome encodes for at least two hundred proteins.

00:02:06: I think its little bit more than two hundred which typical for herpes viruses.

00:02:11: they have alot of proteins can do alot different things.

00:02:15: some them are redundant and CMV actually lose some of the genomes still be able to infect and replicate.

00:02:24: The particles are approximately two hundred nanometers in diameter.

00:02:29: We have the genome on the inside and that's protected by a capsid, then outside of the capsid there is a layer of protein called Dagomand kind of looks fussy when you look at it under an electron microscope.

00:02:43: Then we have the envelope.

00:02:45: so theres'a little bit layer here.

00:02:47: And this envelope has a tonne of different spike proteins.

00:02:50: So its not as simple SARS-CoV-II where there's one spike protein or influenza, whereas two spike proteins.

00:02:58: Here we have a large number of spike proteins that can form different complexes and depending on what type of cell the virus infects it uses different glycoproteins, different spikes in different complexes for those.

00:03:12: For example they are three glycoprotin spikes called GH, GL & GO.

00:03:18: They can form a trimer That's used by the virus to get into fibroblasts, which is one type of cells.

00:03:26: But there can also be a pentamer complex that's made out of the spike proteins G-H, G-L, U-L hundred twenty eight U-l hundred thirty and U- l hundred thirty one A. so let's five...that's why it called the Pentamer Complex.

00:03:42: And thats what the virus uses for getting into endothelial and epithelial cells.

00:03:47: There's also a GB glycoprotein, a GM-glycoproutein and GN-grycoprutein.

00:03:52: So there are large variety of spike proteins on the surface.

00:03:55: that makes it relatively complex to develop vaccines for example because they're so many different ways of the virus to get into different types of cells.

00:04:05: And what has been said is that CMV can infect many different type of cells.

00:04:11: In most cell it goes in a little replication cycle which means that it infects the cell.

00:04:18: It uses this cell as virus factory, more infectious viruses produced.

00:04:23: The virus replicates and at some point the cells dies with a lot of more infected viruses produced.

00:04:33: but thats not only way for CMV to infect cells.

00:04:36: CMV can also get into cells and become latent in there meaning basically just stays there, it doesn't do much.

00:04:45: The cells carry its genome on and then it's basically impossible for the immune system to find out that cell is actually infected.

00:04:56: This happens in specific types of cells in a human body That are part of innate immune systems Typically monocytes which are cells that can differentiate in macrophages or dendritic cells.

00:05:10: And what happens here is the virus goes in, but it doesn't replicate.

00:05:13: It moves its genome into the nucleus of that cell and basically deposits it there.

00:05:20: That's called an episome You can imagine like an extra chromosome in that cell nucleus.

00:05:28: They just stays there Can stay for years or forever Basically life long potentially.

00:05:37: But you also that virus can also be reactivated.

00:05:40: And when it's reactivate, then this virus basically starts to become lytic in the cell.

00:05:47: so it starts to replicate and the cells start producing a lot of viruses, infectious virus... ...and eventually dies.

00:05:54: So the virus can go from latent to lytic to produce more virus but again many years after that cell was infected.

00:06:05: And this reactivation can happen because of stress or the immune system can control infection that well anymore.

00:06:14: Typically when you get an infection with CMV, if you have an immune response and your immune system basically keeps the virus in check You'll get antibodies to at least not completely neutralize the virus can keep it under control.

00:06:31: You get diesel responses, the virus actually counteracts these diesel responses with a number of mechanisms.

00:06:37: but still there's immune control right?

00:06:39: And so typically in the long run the virus can't do that much damage because the immune system keeps it in check.

00:06:46: But thats not always the case and we'll get to diseases That can be caused by CMV and are associated with CMV infections.

00:06:56: A little bit about the history.

00:06:58: It's very likely that this virus is in humans for a very long time and it evolved with us, but was discovered by German pathologist Hugo Rippert in eighteen eighty one.

00:07:13: He didn't really discover the virus But he described enlarged cells With enlarged nuclei from.

00:07:24: he got from a patient and that's basically a deltail of a CMV infected cell.

00:07:31: And, this is actually where the name comes form right?

00:07:33: Cytomine Cell.

00:07:35: Megalo means big right.

00:07:37: so cytomegalovirus means virus that basically causes cells to get bigger.

00:07:46: So it was first description at least for cells that seem to be infected with CMB and the virus was then isolated in nineteen fifty six, nineteen fifty seven around that time by a guy called Thomas Huckly Weller.

00:08:00: And Thomas Hucklewell is famous.

00:08:02: he was at Harvard at that time I believe but his famous because he co-discovered Bolio Virus... ...and he got the Nobel Prize for it together with John Anders and Frederick Robbins.

00:08:14: think that was in nineteen fifty four if i remember correctly am not hundred percent sure but so he isolated the virus for the first time.

00:08:23: How does this virus get transmitted?

00:08:25: There's many different ways how you can get infected with it, the prime infection route is bodily fluids.

00:08:31: saliva blood urine tears sperm can all contain CMV and can lead to CMV infections.

00:08:40: some modes of transmission are kissing basically sexual transmission is very common.

00:08:46: But then there are other modes of transmission too, for example if somebody is CMV negative but gets an organ transplant from a CMV positive person.

00:08:56: Then this person can get infected with that organ and it could actually be highly problematic because people who get transplants typically are immunosuppressed so their immune system isn't super active Because otherwise the body would reject the organ then can lead to uncontrolled infection with CMV.

00:09:18: And another way is from mother-to-baby via the placenta, and that could also be highly problematic.

00:09:26: but we'll get into these cases.

00:09:28: Regular infections in immunocompetent individuals or healthy individuals are mostly asymptomatic.

00:09:35: so you have this initial infection... ...and up to ninety nine percent of cases are asymptomatic infections.

00:09:44: But there can be symptoms.

00:09:46: They can be flu-like, they can be infection of the throat so basically a sore throat.

00:09:52: The salivary glands get infected.

00:09:55: There could be small lymph nodes.

00:09:57: Sometimes people develop low grade fever that comes back every day I think often in the afternoon And this can happen for weeks.

00:10:09: Elevated liver enzymes are a deltail sign.

00:10:14: In this case of a CMV infection, people can have symptoms that are similar to an Epstein-Barr virus caused monocytosis.

00:10:24: Very rarely these infections also lead to complications like Guille Paris syndrome where the immune system then attacks their nervous system but typically the infection is controlled quickly by the immune systems.

00:10:41: in healthy individuals.

00:10:43: It's just that the virus stays forever because it manages to get into these monocytes and basically stays there in the nucleus with its genome deposited there as episome.

00:10:56: Reactivation can happen once in a while, for example because of stress.

00:11:01: A CMV is found in astronauts when they are at an international space station or exposed than usual.

00:11:13: There was also a recent paper that described people who have COVID-IX, I had some reactivation of CMV and it's actually higher in people with long Covid but there are not many consequences if the infection occurs to healthy individuals.

00:11:34: Actually, sixty to seven percent of adults in high-income countries are positive for CMV and almost a hundred percent of adult in low income countries is positive.

00:11:47: So this is very widespread infection.

00:11:50: people often get the infection when they're kids.

00:11:53: The problem as I mentioned earlier is immunocompromised patients here specifically also organ transplant patient but also individuals living with HIV, specifically if they have a weakened immune system and have progressed towards AIDS.

00:12:10: There are certain cancer types that make people very susceptible to disease from CMV And what can happen in these individuals is the virus basically either starts spreading when it's an initial infection or gets reactivated and then this can lead to liver inflammation, liver infection CMV related hepatitis.

00:12:33: This can happen...can lead to eye infections like retinitis for example.

00:12:39: what's a pretty big problem is infections of the GI tract colitis.

00:12:45: so that's the infection or the inflammation of the colon.

00:12:48: And it could lead things like perforation which is really problem and can lead to of course mortality as people can die from that.

00:13:00: Neumonitis, so infection of the lung, esophageitis is something uh that's often described with CMV infections in immunocompromised patients Of course.

00:13:12: what can also happen then if you're talking about an organ transplant patient with a CMV infection?

00:13:22: So, all of these things can also lead to severe complications.

00:13:26: And so in individuals with compromised immune system for whatever reason CMV can be a pretty big problem.

00:13:34: The other problems is congenital CMVs or basically CMV infections that are given from the mother to the fetus usually through the placenta and there the virus can do a lot damage.

00:13:48: Typically around five out of a thousand babies are born with a CMV infection.

00:13:55: The good thing is that most of them are fine, eighty to ninety percent or okay they will not have any complications.

00:14:03: but in the remaining ones there can be birth defects like microcephaly.

00:14:08: so basically smaller brain brain calcifications.

00:14:13: this can lead to deafness and it also can be vision problems infections with CMV in the fetus, developmental delays.

00:14:24: So there can be a lot of big issues with babies born with CMv and the biggest problem here is that moms who are CMV negative become CMV positive during pregnancy And this acute infection then leads often to transmission off the virus through the placenta to the fetuses.

00:14:47: so thats second really big issue that we have with CMV.

00:14:52: But to be honest, I think if you look at all the data CMV in general, CMV infections are also not so great for healthy individuals.

00:15:02: there a lot of different diseases that has been associated now with CMB and number of cancers.

00:15:10: Mukwabidermal cancer is basically salivary cancer and salivaric cancer.

00:15:18: There are some associations to prostate cancer, breast cancer, ovarian cancer and glioplastoma.

00:15:25: I don't know how robust the data there is but that's at least an association.

00:15:31: That's also in association with diabetis which has Alzheimer's disease as well as artyosclerosis.

00:15:38: so it seems that CMV really a risk factor for these things.

00:15:42: What has also been shown is that CMV seems to drive immunosin essence.

00:15:47: Immunosin Essence basically a weakening of the immune system as you get older, and it doesn't respond well anymore in all individuals compared with younger people.

00:15:59: That's what we call Immunosen Essence And CMV seem have an influence on that too.

00:16:05: So In general The virus is widespread.

00:16:08: Most people are infected.

00:16:11: In many health individuals, the virus doesn't cause huge issues but it probably drives disease to a certain degree as well.

00:16:20: even in healthy individuals.

00:16:23: And again and people who are immunocompromised or in pregnant moms this can lead to bigger issues.

00:16:34: There are some treatment options for CMV which is good.

00:16:38: there are polymerase inhibitors that inhibiting herpes viruses in general, or specifically CMV.

00:16:45: They include Gansiclovir.

00:16:47: that's a drug often used and then there is also Cetophovir can be used if there already gansiclavir resistance.

00:16:55: There are some other drugs similar as I said they're polymerase inhibitors.

00:17:00: so their nucleoside analogs look like bases would be incorporated into the genome by the polymerase, but then they kind of basically inhibit that function or lead to apparent genomes and is a function.

00:17:19: And there's another class of drugs which can also be used are terminase inhibitors specific for CMV.

00:17:27: as far There's also a way of treating with antibodies.

00:17:39: What is done here is, antibodies are purified out of plasma.

00:17:44: Antibodies that are specific for CMV.

00:17:47: they're concentrated and it's called CMV hyperimmune globulins And can be used as purified preparations and can be given to people either prevent or suppress CMV replication.

00:18:04: So there are some treatment options here and There's also a lot of development in terms of vaccines for CMV.

00:18:13: But this is relatively complicated because all these different spike proteins In the way you don't know what to focus on when developing vaccines, right?

00:18:23: Nevertheless.

00:18:24: There's a number of vaccines in Different clinical phases.

00:18:27: most of them are in phase one or phase two.

00:18:30: They're recommended protein vaccines For example based on Gb spike protein, there's DNA vaccines.

00:18:38: There are viral-vectoid vaccines that are in development and the thirdest was an mRNA vaccine developed by Moderna a while ago.

00:18:46: with mRNA it is easier to make these spike complexes.

00:18:50: These glycoproteins are hard to purify but you can basically have the mRNA encode when you vaccinate people.

00:19:00: it's made in their own cells and that makes it a little bit easier.

00:19:04: And so there was a lot of hope, the Moderna mRNA vaccine against CMV would work on.

00:19:10: that actually went into phase three trial in pregnant moms but they had recently relatively disappointing results.

00:19:19: I think the efficacy were somewhere between six and twenty-three percent terms of preventing CMV infection in pregnant mothers.

00:19:27: That's, of course not going to work out so that development was stopped.

00:19:32: So I hope some other candidates will have better results because it would be good for a vaccine specifically for pregnant women that are CMB negative to protect them from the CMV infections during pregnancy.

00:19:51: A very interesting herpes virus, I'm pretty sure we'll learn much more about the damage that it can do in the next few years.

00:20:00: There are a lot of these longitudinal studies ongoing.

00:20:02: That's also how We learned about connection between Epstein-Barr virus another one of this herpes viruses and multiple sclerosis And so i am pretty sure there will be Very interesting findings with CMV in future as well.

00:20:17: Just to summarize Interesting herpes virus that probably has been in humans for a very long time doesn't cause A lot of issues In healthy adults, although there might.

00:20:28: There's a lot of associations with diseases.

00:20:32: That it might Cause or Influenced along in the long run but It's a pretty big issue in individuals that are immunocompromised Or in pregnant women because they can spread to the fetus?

00:20:48: Thanks for listening.

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