Theo Geijtenbeek: "Without SHM, we would simply never know that certain trends existed."

Theo GeijtenbeekProfessor Theo Geijtenbeek has served as one of SHM’s advisory board members since 2013. We caught up with him recently at the AMC to discuss how, as a basic scientist, he fulfils his role on SHM’s advisory board and how his group’s work on dendritic cells led to a paper in Nature that made the news a few months ago.

Could you tell us how you came to be working on HIV?
I actually started out in the field of chemistry, although my PhD did have a more biochemical focus, looking at phospholipid transfer proteins. After that I wanted to do something different and applied to work in immunology with Yvette van Kooyk in Nijmegen (now based at the VUMC). Although I knew nothing about immunology, I did have a strong molecular background, which was what Yvette was looking for. Initially I worked on leukaemia and at some point I embarked on a so-called Friday afternoon project. Someone in the lab was working with dendritic cells (DCs, the immune cells that I now work on) and I had developed an assay that allowed me to study binding of adhesion molecules. So I borrowed these cells to see if the assay worked on them too. Surprisingly, the binding was the strongest I’d ever seen. We were quite intrigued and, even though we thought it might be an artefact, I started to look into it further. Eventually, I discovered a protein on DCs that no-one had found on these cells before, which we called DC-SIGN. The literature vaguely mentioned that this molecule might bind HIV and so I went to New York to pursue this line of research further. Eventually I found out that DCs actually transmit HIV to T-cells. It turned out to be a very important discovery and led to several great papers. That’s really how it all started and how I became interested in viruses and the mechanisms they use to escape immunity.

Later I started my own group at VUMC. However, VUMC focuses more on tumours than infection, so after a few years I moved to the AMC, where I became professor. I am now head of the AMC’s department of experimental Immunology (EXIM), which also includes another HIV research group and all the biobanking for the Amsterdam Cohort Studies. This has proven to be very useful for my research and has provided many opportunities. Even though we carry out fundamental research, we’re very close to the doctors here and so it’s easier to be involved in clinical research or get ideas for research from the clinical setting. Vice versa, people here are also far more interested in dendritic cells now that I’m here. So it’s a win-win situation and I really enjoy working here.

You are also a member of Stichting HIV Monitoring’s advisory boardWhat is your role on the board?
Well, I’m kind of the odd one out because I´m there to give the basic science angle. But it is important that someone fulfils this role on the advisory board. I see my role as looking for links between particular trends and basic immunology, since many mechanisms or trends can be explained by the underlying immunology. For example, a few years ago SHM reported that people living with HIV were also more likely to become infected with HCV through sexual transmission. Interestingly, at the time, acquiring HCV through sexual intercourse was not thought to be possible. This was something I felt I could contribute to. While I I couldn’t explain it straight away, I could offer suggestions as to why it might be the case. In fact, we eventually followed it up with a series of experiments that, with the help of several clinicians, turned into a small, successful line of research in our lab.

How does SHM’s monitoring work affect your research?
It’s very important for my research that there’s an organisation like SHM that highlights trends. This can either help us understand something or prompt us to investigate it further, just like we did with the link between HIV and sexual transmission of HCV. It provides us with new research ideas, gives our work relevance and, more importantly maybe, means both fundamental researchers and doctors can’t ignore trends and, instead, have to take action. Without SHM, we would simply never know that certain trends existed.

So the link between fundamental research and the clinical setting is important to you?
Yes, I really feel it is important that my group is able to translate their research to a wider setting. That’s why we feel the annual NCHIV meeting that SHM helps to organise is so important. We spend a lot of time adapting our abstracts and presentations for the NCHIV audience, bearing in mind what clinicians and the wider public would find interesting about our work. It’s quite a challenge, but worthwhile.

Coming back to your research, does your group only work on DCs?
Basically, yes. In terms of HIV, it all started with the discovery that DCs bind HIV very strongly through the protein DC-SIGN. This allows the DCs to very effectively transfer HIV to another part of the cell for replication. In addition, we are also looking to see whether DC-SIGN is involved in facilitating the replication of other viruses. Moreover, DC-SIGN also binds mycobacteria and fungi, so we are also investigating these pathogens.

We also work on Langerhans cells, which are a subset of dendritic cells located in the upper layer of the skin and mucosal tissue, and are the first cells that pathogens encounter. When I first started at VUMC, it was assumed that Langerhans cells acted the same way as DCs to facilitate HIV transmission. However, during my time at VUMC we found that LCs don’t act in the same way as DCs, due to the presence of a particular cell surface protein, Langerin. This is something that we’ve continued to work on.

Was this the work that led to a recent paper in Nature?
Yes. The work was carried out by Carla Ribeiro. We were working with the idea that the presence of Langerin prevented transmission, but we had no evidence of the mechanism. When Carla joined our group, she had some ideas about looking at the role of autophagy, the process by which cells break down unwanted cellular components. This is easy to measure and we found that when autophagy was interrupted, transmission took place, just as in DCs. Carla subsequently looked for the link between Langerin and autophagy and found that a protein called TRIM5α was necessary for autophagy. The funny thing was that everyone was sure that human TRIM5α didn’t play a role in HIV infection. However, it turned out they were all looking at the wrong type of cells, because when Carla studied LCs, she found that Trim5α acted as a restriction factor and was very effective at blocking HIV infection.

How does Trim5α work?
Trim5α plays a role in initiating assembly of the structure required for autophagy and the formation of autophagosomes that remove and break down HIV. In Langerhans cells, Trim5α is attached to Langerin. We also looked at a virus that didn’t bind to Langerin, and found that in this case Trim5α doesn’t do anything. Similarly, if we use a mutated form of Langerin, Trim5α also remains inactive and the virus can enter and infect the cell. Even more importantly, we found that Trim5α also causes autophagy of Birbeck granules containing HIV particles inside the cell that are waiting to infect a CD4 cell. So, overall, Trim5α makes the whole Langerhans cell far more efficient in breaking down organelles that contain HIV. It really is very effective.

What are your plans for the future?
Carla is very interested in investigating whether we can stabilise Trim5α in DCs. We have found that, in dendritic cells, DC-SIGN also binds Trim5α. However the moment HIV binds to DC-SIGN, Trim5α is released. So, when HIV binds Langerin, Trim5α is activated, but when HIV binds DC-SIGN, Trim5α is deactivated. Therefore, if you can prevent Trim5α from detaching from DCs, it might be possible to make DCs block HIV infection rather than promote it. Secondly, Trim5α also exists in T-cells, but it seems to have a different function. We therefore also want to find out how Trim5α works in T-cells and possibly modulate its activity in T-cells as well. Finally, Carla has shown that autophagy has an antiviral activity. The next question is whether we can amplify autophagy in certain cells and stimulate degradation of HIV. This could be a good therapeutic target, because autophagy activators or inhibitors are already being used as treatments in other fields, so it should be easy to develop them further for HIV.

We are also trying to take a more translational approach to our work. It’s very encouraging to see how our fundamental research (for example with DC-SIGN) can contribute to a better understanding of a disease or the development of a treatment.

Where do you think we’ll be in 10 years’ time?
Perhaps we’ll have a treatment to stop transmission. In terms of chronic infection, it may be useful to be able to activate autophagy at a very early stage, thereby keeping the viral load low and preventing reservoir formation. Ultimately this might help towards finding a cure or at least help to strongly limit virus replication and thereby prevent co-morbidities or adverse effects of chronic infection.