Questions and AnswersDr. Michael Zwick

Your research topic is the Human Immunodeficiency Virus (HIV). HIV or AIDS is nowadays said to be an “old disease”, but still no effective vaccine has ever been found. Isn´t that a little frustrating for you as a researcher?
No, it isn´t. From a scientific point of view, HIV is a very interesting pathogen. The virus is so difficult to study because of its variability and its ability to evolve and adapt to any therapy. But also from a social point of view, research on HIV is a big challenge: As long as we don´t have a vaccine against the virus, we, the scientists, have the duty to continue until we find something that works.

What is the current state of research on HIV? And what are you and your research group doing exactly?
What we currently know is what certain binding sites on the virus look like. Antibodies to these sites are produced only rarely by the immune system, but when they do they can bind and eliminate the virus. Right now, we can break it down to about 4 or 5 different classes of antibodies each of which targets a specific site. One of these sites is located close to the membrane near the base of the spike of the virus. That´s the one I am especially interested in. We and other research groups as well are analyzing the antibodies that fit on this site. However, studying antibodies for vaccine design is unlike studying the effect of a single drug against a single receptor. When you investigate the drug, you know the exact mechanism, you know what the molecule looks like and you know that the receptor does not change. It´s completely different when the immune system produces antibodies as a response to the virus or a vaccine, because every antibody is different and has a different mechanism of neutralization. Another problem is that the viruses’ envelopes are very heterogeneous. Even in an infected individual you will find thousands of different virus envelopes. So we have to take a basic approach and study each class of antibodies, figure out what they look like, what they are binding to and at what time during the entry of the virus into the cell do they block. We look at the antibodies on a case-by-case basis and look for patterns and clues. 

So to find a vaccine you will have to find regions of the virus that do not vary as much...
Yes, that´s what we are doing. We study phylogenetic trees of the virus. We examine the molecular evolution of the virus to find out where the conserved regions of the virus are located, namely those structures that do not change much. The epitopes, which are the part of the antigen that is recognized by the antibodies, on the base of the envelope spikes on HIV are very conserved. That is what makes them interesting for the development of a vaccine. Yet still, it is quite difficult to elucidate the structure and the function of these molecules. Unlike other antibodies, they have very hydrophobic structures, which makes them unusual and challenging to investigate. Another problem that we encounter is that even for a single virus it is very difficult to generate neutralizing antibodies. The problem is not producing antibodies in general, but that they quite often will bind in vitro - however in vivo, they are not effective. It is a greater problem with HIV than with many other viruses, and we are trying to understand exactly how this happens.

Some years ago, news arose about people who were immune to HIV. By analyzing their immunity, researchers hoped to find a vaccine. How did that work out?
The small number of people who are frequently exposed to the virus, but who do not become infected, have been studied over the years and they have played an important role in a few discoveries. For example in the discovery of the co-receptor, a site on the host’s cell that HIV needs to enter into the cell. People that are immune to HIV have a genetic mutation in this co-receptor and therefore don´t get infected. These discoveries have been important in understanding the mechanisms of HIV infection and provide clues for stopping it. But we still have to deal with perhaps the biggest challenge of all, which is to develop a vaccine. For the development of a vaccine, we will have to use adaptive immunity in a way that will work for all human beings. We will have to find good antigens that will induce an effective response by the adaptive immune system. 

Are you optimistic about finding a vaccine against the disease some day?
In the absence of an actual vaccine, we have to be careful in saying `yes, we will definitely get it´. However, I can say that our research field has improved a lot. Right now, we have good clinical cohorts to find patients. That wasn’t always the case. Also, the field of crystallography has evolved a lot and other structural biologists are helping us elucidate the structure of antibodies and antigens as well. And we have considerably improved our methods, which helps us work faster. Actually, there are a lot of new antibodies coming out that are effective against a lot of strains. This is quite encouraging. I think that the problem to get a vaccine should be solvable in principle. Perhaps not against all strains, but one that will protect against some HIV strains will be a huge start.  

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