Researching Human Cytomegalovirus: Q&A with Dr Ben Krishna

Sidney College Research Associate Dr Ben Krishna is a virologist and immunologist. Originally from Hertfordshire, England, he studied biochemistry at Oxford before completing his PhD at Cambridge. He then spent two years in the USA, working at The Cleveland Clinic, where his work included researching the SARS-CoV2 virus.

Ben’s current research focuses on understanding and developing treatments for Human Cytomegalovirus, or HCMV, a member of the herpes family and one of the most complex viruses yet discovered. Over three quarters of the world’s population carries HCMV. Most of us will never be aware we have it, but it can cause congenital birth defects when the virus infects a growing foetus and serious, even fatal, disease in people with compromised immune systems.

So where did your interest in virology and immunology come from?

“Well, I studied biochemistry, and my interest was in proteins, and specifically how you make a drug that stops a protein from working in a particular way, which is basically how medicines work at an almost atomic level.

“I had to do my final year project and I guess, like a lot of undergraduates, I didn't really think too much about what I was doing: I just picked a lab and started working there.

“That lab was looking at HIV, how antibodies against HIV work, and that started everything for me. It was really interesting to understand how this virus can adapt over time, how it can stay in one person and persist in that person for the rest of their life.

“I just found it fascinating. So, I decided to do a PhD in viruses and immunity.”

You have worked on COVID and HIV, and you are now looking at HCMV, so how do you design a drug to block or suppress a virus? And what role do proteins play?

“So, yes, a virus has its own genome. Within that genome there are going to be individual genes and those genes code for certain proteins. So, the most famous example right now would be SARS-CoV2 that causes COVID-19, that has this spike protein that everyone always talks about. The spike protein is on the surface of the virus and it sticks to a protein on the surface of the cell, called ACE2, and then the virus uses that to get in.

“So, the way the COVID-19 vaccines work is they train the immune system to make antibodies that get in between those two proteins. Spike and ACE2 can't stick to each other anymore and, as a result, the virus can't get into the cell.

“Antivirals are usually molecules that stick to viral proteins and stop them working. Imagine sticking a clamp into a bicycle wheel, that will physically stop it spinning. Antivirals do this but at the atomic level.

So how does a virus like SARS-CoV2 or HIV compare to the Cytomegalovirus?

“At a fundamental level, SARS-CoV2 has about twenty-six genes, HIV has about nine. The virus I am working on, Human Cytomegalovirus or HCMV, has over two hundred genes. So, it's a much, much bigger virus. It's got loads more proteins. Those proteins do lots of stuff that these smaller viruses don't do and a lot of what it does is not very well understood.

Does the complexity of HCMV, then, make the challenge of finding a solution harder?

“Yes, with a virus like HIV there are only so many targets, but with HCMV there are loads of things we could be interfering with that might be helpful, we just don't know enough about them yet.”

So, for those who don’t know, what are the key characteristics of HCMV?

“Firstly, most of us are already infected with HCMV and once you’re infected with HCMV you’re infected for life.

“Most people won’t realise that they are carrying HCMV as their immune system keeps it under control, but HCMV is a serious threat to people with compromised immune systems, so that would include people born with faulty immunity genes, people living with AIDS and people who have recently received organ transplants. HCMV infections of pregnant people can also be a threat to the developing foetus.

“There is no vaccine for cytomegalovirus, and the current treatments are fairly unpleasant antivirals.”

So we’re talking on the eve of World Health Day, which this year marks the 75th anniversary of the founding of the World Health Organisation. Is the threat posed by HCMV particularly relevant to developing countries?

“Yes, the threat of HCMV is very different depending on if you're in a developed country or developing country. In a lot of developing countries, HIV and AIDS are still a really big problem, and HCMV is one of the many problems those people are going to experience.

“In the developed world, HCMV is associated with transplants. In general, organ transplants are really successful these days. We've got very good at doing them, and the number of transplants we're doing is going up each year because you can use organ transplants to treat all sorts of things these days. But HCMV is still a really big issue.

“The problem arises because the anti-rejection drugs given to transplant patients are not specific to stopping you rejecting an organ, they just stop the immune system from recognising infections for a while.

“If you are healthy and you're infected with HCMV, your immune system will suppress the HCMV, but it won’t clear it: it can’t.

“The virus will remain in your body and it will be waiting for an opportunity. Immunosuppression allows the virus to start spreading through the person.

“When it does that, you will get all sorts of different symptoms, because the virus infects all parts of the human body. So, you can get pneumonia, so the lungs, you can get hepatitis, so the liver. You can get infections of the pancreas, you can get infections of the guts like gastroenteritis and those sorts of problems. And classically, and really more for people with HIV, you see retinitis, so people will start losing their vision, and retinitis is very hard to treat.

“One of the early symptoms of AIDS was that the patient’s vision would start to go blurry. That wasn’t HIV, it was because their immune system couldn't control the HCMV.”

So how do we currently treat HCMV in these post-transplant patients?

“In some countries, as soon as you've had your transplant you will be put on immunosuppressants and they will start giving you HCMV antivirals straight away, to try and stop the HCMV from coming out.

“In other countries they will monitor you, so they'll be taking blood samples from you on a daily or weekly basis. If they see HCMV start to build up, then they'll start treating you with drugs.”

So what specifically are you looking at?

“The lab I work in is with Professor James Nathan who is an expert in respiratory medicine and particularly this state called hypoxia, which is where you are not getting enough oxygen circulating around the body.

“I am interested in hypoxia because when you do an organ transplant, the organ that is donated for transplant is temporarily deprived of blood supply, and so that organ will go into a hypoxic state. I want to understand how that affects the virus because - and my study is still at a preliminary stage - I think that temporary hypoxic state might actually help the virus.

“You might have someone with HCMV donating their organ to somebody who doesn't. And so it might be that the HCMV in the oxygen-deprived organ actually gets enacted and reactivated by the hypoxic state before it is transplanted into the recipient. If that is the case, it would actually make the situation a lot worse, because you're not only undergoing a transplant, you’re also immunosuppressed and you’re potentially being given an organ with lots of active HCMV in it. I think that might be a really big problem in the current way we do transplants.

“So, my focus is on whether hypoxia causes the virus to reactivate and start spreading.

“I am also looking at why the virus would evolve to do this, because we've only been doing transplants for thirty years and HCMV is really as old as humanity.

“If it has evolved in this way, it must have done so for other reasons. So, I'm trying to understand what's going on in the body and why the virus might want to respond to these states and that's perhaps more to do with inflammation and spreading from one person to another – that part of my research is quite speculative at the moment."