Interview with the 2008 Nobel Prize laureates in Physiology or Medicine Harald zur Hausen, Françoise Barré-Sinoussi and Luc Montagnier, 6 December 2008. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.

Luc Montagnier, Harald zur Hausen, Françoise Barré-Sinoussi, congratulations on the award of the Nobel Prize in Physiology or Medicine and welcome to Stockholm.

Luc Montagnier: Thank you.

Françoise Barré-Sinoussi: Thank you.

Harald zur Hausen: Thank you.

The work for which the prize has been awarded was done a good quarter of a century ago, and so I imagine you’ve all allowed yourselves the luxury of imagining yourself here once or twice, so is it a huge surprise to find yourselves here?

Françoise Barré-Sinoussi: For me yes, yes it is, I never thought before, to be here one day. Surely because working on the HIV/AIDS I thought that probably you will need a vaccine to have a Nobel Prize one day for this disease.

Hopefully we’ll talk about the need for a vaccine soon.

Harald zur Hausen: I must say I have heard some rumours before that I’d been proposed a few times, but I didn’t expect it this year. Last year the rumours were a little bit more dense, then there was a suspicion that it might happen, but this year I didn’t think of it, so I was working in my office when I received the phone call and this was really a full surprise.

Luc Montagnier: I also, I was nominated several times and knew from some colleagues, but that of course it’s like the Oscar, you live with that, everyone knows, you’re getting out from the hat so it was a surprise also I must say, in Ivory Coast.

That’s right, yes, you were in the Ivory Coast and Françoise Barré-Sinoussi was in Cambodia.

Françoise Barré-Sinoussi: Cambodia.

Your positions when the call came indicate the global nature of the AIDS epidemic.

Luc Montagnier: Absolutely, it was symbolic.

Françoise Barré-Sinoussi: I think that was important.

Again, something we’ll come to in a little while. This year’s prize has been awarded for work on two viruses, human papilloma virus, HPV, and human immunodeficiency virus, HIV, and the work on these two viruses indicates two very different timelines of research for discovery. in HPVs case it took you, Professor zur Hausen, a full decade to convince the community that your hunch that HPV was responsible for most cervical cancers was correct. How did it feel to have a hunch that you had to keep for ten years while working on it?

Harald zur Hausen: Let me say it this way, it’s true what you said, I mean it took about ten years or so before we were able also to prove our point, but in a way there’s some, in my opinion, there’s some similarity between AIDS and cervical cancer research said this way. It’s of course a problem of enormous magnitude, particularly in the ECS right now, killing an enormous number of people. Cervical cancer has been a problem of enormous magnitude over decades, a million year really, because it’s probably with us since the early time of mankind. In a way these are both conditions which are quite important, the agents causing them are quite different, I mean they are really different, and so research followed different pathways in a way, but I think looking at it from the viewpoint of public health these are both problems of certain importance.

Certainly, yes, that unites the discoveries. But just getting back to this timeline thing, were there times during your ten-year search for the proof that you thought of abandoning the project?

Harald zur Hausen: No, not really, because I must say I was very convinced that we were on the right track from the beginning really, because first of all we had seen that the existing number of anecdotal reports are from malignant conversion of genital warts, and secondly already since the 1930s there are examples available where at least in animal systems papilloma virus has caused cancer. So it was not that farfetched to research carefully in human cancers as well, and cervical cancer was a good example. It was not well received in the early days it’s true, because another virus had been suspected at that time, namely inner genital herpes simplex type II infections, but I must say really we were convinced during this period that this was the right way to go and so we pursued it intensively.

Was it possible to convince the funding agencies as well?

Harald zur Hausen: I must say in Germany it was very good, because I returned from the States and I applied very early for research on papilloma viruses, and at least my scientific colleagues who evaluated those applications apparently were positively impressed and granted the money, so we were well supported during this period of time.

In the case of HIV the work that you did happened within a very short space of time, the initial work, it was less than a year between you starting to work on this mysterious disease which was made to be known as AIDS, and you coming up with a novel anti-virus that you called LAV and became HIV later, so the pace of research must have been frenetic at that time?

Françoise Barré-Sinoussi: Yes, it went very shortly to isolate the virus on the first patients, when we obtained the first lymph node from clinicians and patients that kindly accepted a biopsy. However, it took several months after to really link this virus to the disease itself.

Yes, that was …

Luc Montagnier: Actually we were prepared because before of course working on the human retroviruses was a long history of working on animal retroviruses, and of course we applied the same technology we have already learned on animal viruses to the human system, and we were lucky to have the first experiments working, that not happen all the time, and so as Pasteur said, fortune smiles to prepared minds.

Yes, you had the system.

Luc Montagnier: We had the system.

Françoise Barré-Sinoussi: I think also the interaction between us and the clinician were very fruitful, because the fact that we chose for the first sample a lymph node biopsy and not taking a patient with AIDS was probably critical because after we learned that lymph nodes are full of infected cells. We decided also not to look after several weeks but to look into the culture regularly, and I think that was also a critical point. Plus the fact that we benefited, as Professor Montagnier said, of the technologies that were available in the lab, plus also the technology and reagents that had been developed at the same time, I am thinking particular about interleukin 2, what was called at that time TGF-β, allowing the T lymphocytes to grow in culture.

It became, as many people have reported, quite a competitive area later on, but at that point, when the epidemic was just beginning, was it a very collaborative field to be in? Were people helping each other?

Luc Montagnier: Yes, I think it was actually, we had a very good relationship with Dr Gallo and his colleagues at the NIH in the United States, and we had access to his reagent to show this virus was different from HTLV-I for the first human T-cell leukaemia virus found in men. And also we had as Françoise said, a good contact with clinicians who we are working now on AIDS, there were very few in France because in that time maybe there were other cases of AIDS, but not in France. We had also the collaboration of a very good electron microscopist, could see the first viral particle one month after we had the culture, and after that we extended our collaboration with immunologists and epidemiologists so that we could have a group which could concur to find this virus as /- – -/ because it was the main … of course /- – -/ virus is good, but was it passenger virus, was it something else, where did it go, this is where the main problem, and in that of course, and my /- – -/ colleagues also quickly contributed.

And presumably it’s essential to have these networks established to some extent before you start the work because it’s quite hard to get them going then, so you need to be …

Luc Montagnier: Yes, we had already some projects to look for viruses involving cancer and leukaemia, so two or three years before we already had a small group inside my research unit with Françoise Barré-Sinoussi and Jean-Claude Chermann to look for retroviruses in human diseases.

Françoise Barré-Sinoussi: And we were looking for example for sequences of retroviruses in breast cancer, in human breast cancer, and we were looking at lymphocytes indeed of women with breast cancer, so this means that the technology was there.

Did that come to anything? Is there a retroviral …

Françoise Barré-Sinoussi: Indeed, we had to stop …

Luc Montagnier: It’s something which still we have to pursue actually.

Harald zur Hausen: There was some interesting report on HERV-K, it’s human endogenous retroviruses …

Luc Montagnier: Yes, they are /- – -/ not complicated because there are other endogenous retroviruses, you know, in the human genome which are there for millions of years, but some of them could be involved in diseases.

So it’s still a very active field?

Luc Montagnier: Yes.

Françoise Barré-Sinoussi: Yes, it’s still.

Luc Montagnier: It is, yes.

If we can turn to application of the discoveries, starting again with HPV, having established the link between these two variants of HPV 16 and 18 research …

Harald zur Hausen: Cervical cancer.

Vaccine development didn’t immediately follow.

Harald zur Hausen: I approached very early in specifically German companies at that time, for a production of vaccines – that was in 1984 – we isolated the two types 16 and 18 in ‘83 and ‘84 and published them in these years. The result was initially a bit disappointing because there was only one company who became interested, namely Behring Company Marburg, who were already at that time producing a number of different vaccines. They funded us even for a certain period of time for a joint project, but then they did a market analysis and apparently the market analysist told them that there is no market for such a vaccine which was of course a total miscalculation. Secondly what I learnt only a few weeks ago was that apparently they did at the same time what they called some tests for the presence of antibodies in normal healthy persons and found that virtually everyone was positive which again is a wrong result because as it turned out later it just doesn’t exist. I don’t know on which basis these tests had been done.

This really delayed, at our place at least, the development of vaccines for quite a number of periods, for quite a number of years in fact. It started only then later when some American companies became interested, the technology advanced to some degree the production of virus like particles became possible by inducing, so to speak, the formation of empty shells of the virus, which are presently being used for the vaccination, and that turned out to be very useful, as a possibility that for the moment some of them being explored right now. But on the whole the vaccine turns out to be extremely effective in presently uninfected persons, and so the efficacies claim to be in the range of 98, almost to 100%, it is very nice. I mean it’s indeed now a possibility to prevent at least something like 70% of cervical cancers, but one should keep in mind that the latency period between infection and cancer development usually takes something like 20 or 30 years, so in order to prove whether cervical cancer is really prevented we would need this period, but at this moment we can look at the prevention of precursor lesions.

And the difference in the percentages is because the vaccine is almost 100% efficient at preventing cancer caused by HPV 16 and 18.

Harald zur Hausen: Correct.

But some cervical cancers are …

Harald zur Hausen: That’s correct, something like 20 or 30% are not caused by these types of virus types, but nevertheless there are some cross reactivity, and some additional types of the vaccine that is likely that its preventive value will be slightly higher than 70%, it’s probably close to 80%. If there’s a cross reactivity.

So there’s now a very apparently successful vaccination programme going on in the, at least in the richer world?

Harald zur Hausen: What you’re saying is really a problem. It’s true that in many countries there is an active vaccination programme going on. In Australia for instance 80% of the prospective age groups have been vaccinated by now, of young girls, and in many other countries, in Germany, something like 40%, I do not know exactly the figures for other countries, but indeed the vaccine is very expensive and for many of the developing parts non affordable. But nevertheless I know now that both of these companies are producing a vaccine, offering specific prices for some parts of the developing world, in my opinion still too high, but there are other companies in China and in India starting to produce vaccines on their own, at least as far as I heard, and so I anticipate that the vaccines will become much, much cheaper in the near future.

Do you think people will regularly accept the vaccination programme in the developing world?

Harald zur Hausen: In the developing world they accept it probably easier than here in the Western countries because what is frequently not recognised is that the infection itself is relatively frequent here too. Cervical cancer is a relatively low because we do have screening programmes which detect early lesions and so remove them then by surgery. We have in Germany for instance 140,000 conisations per year that takes a piece out of this cervical canal with a number of complications subsequently, two to seven percent of complications which arise subsequently, so I think here we should make much more. There is the populations are being made much more aware of the fact that it’s so much important to prevent the precausal lesions in order to avoid the surgical operations than really cervical cancer which of course in our country for instance is about close to 6,000 cases per year.

Do you think that there’s also a case for vaccinating men as well as women?

Harald zur Hausen: Yes, I personally I very strongly agree, not all of my colleagues do the same, but I’m doing it for several reasons, because first of all one of the vaccines also contains a vaccine against genital warts, the type 6 and 11, which is a nasty and very unpleasant condition affecting males as well as females. Secondly anal cancer which is caused by the vast majority to the same types of viruses, 16 mainly and 18. It’s more frequent in males than in females, and so about 25-30% of all oropharyngeal cancers which are linked to the same types of virus infections, and again they are more frequent in males than the females. I always argue this is also a question of gender solidarity, I mean the infection is transmitted from males to females as well as vice versa of course, so for all these reasons I’m very strongly advocating also to vaccinate males, boys in fact.

But there hasn’t been any programme so far?

Harald zur Hausen: The problem is that the health insurance is at present not willing to pay for it, you can do it privately because the health insurance are not covering it because they think the cost benefit ratio is not good enough to vaccinate boys. But I hope it will change, particularly when the vaccines become cheaper.

Thank you. Turning to HIV, the HIV story is one of in fact incredibly rapid therapeutic development, that by the end of the 1980’s there was anti-retroviral therapy around, and that …

Luc Montagnier: Only if you /- – -/ 1996, so there’d been a gap of about 10 years in which many people died before we had the efficient treatment. But a bit quicker also for those patients that yes, looking at history remarkably short …

Yes, and now that it is an efficient …

Luc Montagnier: It is efficient but it’s not a cure, this is the problem. It’s not a complete cure, it cannot eradicate the infection.

Exactly, and this is what I was going to get to, because you need to keep taking these medicines.

Luc Montagnier: Absolutely, every day.

And that means that it really is a solution only for those who can afford them and get their hands on them.

Françoise Barré-Sinoussi: There is of course, I mean we have to find other solutions, however it brings quite a lot of benefit to the patients in our countries. We consider today that the patients on the treatment have a chronic HIV infection and treatment. It has been also some progress, not enough, but some progress in developing countries, five, six years ago only 2% of patients that needed to be treated were treated, today 30% of them are treated, so there is progress. Of course that would be very difficult to reach the objective of the United Nations to have everybody that needs to be treated in 2010 in less than two years, so I think that the goal will not be reached. However, we have really to fight to try to approach this reach as soon as possible for the patients all over the world. Meanwhile we still have to work and to have other solution for avoiding the long-term treatment.

I was going to ask about the potential for the vaccine development, both preventative and therapeutic.

Françoise Barré-Sinoussi: First of all, maybe before speaking about vaccine, we have to consider that treatment probably will be preventing cases of infection, because patients that are under treatment have a low viral load including in genital secretion that means that they transmit less of the virus when they are under treatment, of course that’s not sufficient and of course we need some other prevention method beside the condom.

Luc Montagnier: Personally I think we should target first a therapeutic vaccine before going to a preventative vaccine, there have been several attempts to make protection, by protective vaccine, complete failure you see, more difficult than the papilloma vaccine. For many reasons, many technical reasons, also the fact the virus changes over time, it’s a retrovirus and still I think it’s /- – -/ but also the papillomavirus I think it’s inside the cell, so it’s not only the only reason …

Harald zur Hausen: There are many differences, yes.

Luc Montagnier: But I think it will be quicker and better to start with the therapeutic vaccine, it means a vaccine given to people which have been already treated , already on antiretroviraltherapy with low viral load but which are infected, to boost their immune system in order to control completely the virus infection. This already shown in nature, there are some few people which are infected but are never sick, never having the immune system repressed, but we can try to have a measure to a patient having this situation.

What have we learnt so far from those patients?

Françoise Barré-Sinoussi: We already learn the patients that are called HIV controllers is less than 2% of people that are infected, they control perfectly well their viral load, and we already learned that at least some of these controllers have developed a sub-population of T cells which are capable to eliminate infected cells. We know that this sub-population of T cells is less activated that the cells that we found in most HIV patients that progress to disease. What we don’t know yet is why this proportion of patients are developing this response, what are the signals that in use this sub-population of efficient CD8 cells, we know that there is some genetic factors that are probably associated, genetic factor does not explain all of it because not all HIV controllers are HLAB 27, B57, and to speak into English, into scientific language, but whatever, that means that genetic factors are probably involved.

Unidentified genetic factors?

Françoise Barré-Sinoussi: There are, some are identifying probably, some are not yet.

How far away do you think a therapeutic vaccine might be at this stage?

Luc Montagnier: It’s very difficult to say because of course for the therapeutic vaccine so many times I know something which was wrong, but I think it could be quicker. Perhaps a matter of several years before we get some phase one and two clinical trial with this kind of vaccine, because the end point is the efficacy to measure, it’s easy to do it, it’s just the absence of rebound of the virus, when they stop antiretroviral therapy, it means the immune system can control the virus, so it’s easy to measure, so we can make more tiers interpreting vaccine than we can do in there. Candidate prophylactic vaccine we should take in phase three, thousands of people exposed to the virus. And like the papilloma virus vaccine it’s unlikely we get 100% protection, and if somebody think it’s probable that he’s not, you know, it’s also very bad situation.

Absolutely, absolutely. If we could speak about the scale of the epidemics, in fact in both diseases, but starting with AIDS. AIDS is close to affecting I think one percent of the world population now, is that …

Françoise Barré-Sinoussi: Yes, there is 30 million of people living with HIV AIDS today.

And it’s increasing very rapidly.

Françoise Barré-Sinoussi: It’s increasing, it’s getting more stable globally, probably because first of all in Africa the estimation was higher than the reality at first, and then secondly we hope that with time and the extension of access to antiretroviral treatment the epidemic will slow down. We can see that already in some countries, for example in Botswana, when you look at the curve of mortality of patients you can see that there is a decrease soon after they start to use widely with antiretroviral treatment.

Right.

Luc Montagnier: The situation is very difficult for some African countries like Western Africa and South Africa, and the country Botswana is an exception because they are smaller, a rich country, but in South Africa for instance about 10% of the population is infected, it means five millions out of 50 million, and we don’t see how we control the situation, it’s very difficult.

Do you feel you understand why the epidemic occurred when it did in the early 1980s? Because I gather that the virus was present in the human population for decades and decades before that it is thought?

Luc Montagnier: What caused the epidemic … Something happened, actually both in some parts of Africa, central Africa but also in North America, in large cities like New York and Los Angeles, in so-called high-risk groups. The homosexuals with multiple partners, drug abuse … My personal vision in that when somebody has a very good immune system he can defend himself against the virus, could be exposed many times and not be chronically infected, but something probably happened in the 70s which increased the violence of the virus both in Africa and the United States, and we don’t know yet exactly what it is.

Françoise Barré-Sinoussi: We have to consider also the evolution of the society because travelling is very common, and even within Africa at one point after the French, the Belgian leave Africa, there was a lot of travelling within Africa, and we can imagine that the virus started to spread at that time in Africa, and of course the liberalisation of sexual behaviour together, that can …

Luc Montagnier: The African virus was not exported first to Europe, it was exported to the United States.

Françoise Barré-Sinoussi: To the United States, yes.

Luc Montagnier: And back to Europe after that.

There are many types of HPV, is it changing? Has there been a rise in cervical cancer do you think, because of changes in HPV over recent history?

Harald zur Hausen: At least in younger people yes, there has been a change, there has been an increase in cervical cancer incidents, though in fact at this moment 114 different types of HPV are infecting humans, so it’s a complicated story in a way. But nevertheless, there are only a limited number of those, something like 14 or 15 types which play a role in cervical cancer, one of them, 16, very predominantly in more than 50% and 18 it’s slightly less than 20%. The virus in contrast to the HIV viruses is very stable, they do not mutate very quickly and they are with us since the early days of our evolution because we do find related types for instance to HPV16 in old world monkeys indicating that the changes are relatively minimal since the splitting of the monkeys, the humans from the monkey family. In a way, so for those reasons we do not expect, even if you vaccinate successfully against cervical cancers, that what we want is frequently being discussed a quick type replacement at some other types of the prominent plays the same type of role, but this has to be seen on the other end it wouldn’t be a problem to include also into a vaccination protocol, so I don’t expect that along those lines very much is going to happen.

Right. Thank you. A question for any and all of you, do you think that viruses will come to play a more important role in cancer in the future? Do you think that we don’t yet fully understand how important viruses are in causing cancer?

Luc Montagnier: I think the candidates retroviruses is also for breast cancer, prostate cancer, it’s possible, and probably also we have to look at infectious bacteria, the microbes, not only the viruses, because cancer to be some factors, you know, to be termed not the only factor, but since cancer is multifactorial probably there are some infectious agents probably like the stomach cancer where you’ve got Helicobacter pylori also.

Also a Nobel Prize …

Luc Montagnier: … two years ago, so I think yes, we should look for more infectious agents in cancer, it’s a way also to protect because we have needs to counteract the effect on viruses, vaccine but also antiviral drugs so there are many possibilities to find viruses and micro variations as well by antibiotics for instance.

Harald zur Hausen: I agree with what Luc Montagnier said a moment ago. Indeed, in my opinion too there are good chances that additional cancers will be linked to viruses in the future. If you look into the discovery of new viruses potentially linked to human cancer it becomes apparent that during the past two years four new types in the papilloma virus group popped up, one by the way here in Sweden. One of them is also linked to a specific type of human cancer, namely the so-called Merkel cell tumours, a relatively rare tumour arising on the immune suppression in the skin and your endocrine tumour. I personally believe that besides breast cancer I also strongly feel that there’s very good reason to search very intensively for viral etiology, leukemias, lymphomas, really cancers where you have very good reasons to search for agents, so right now from epidemiological grounds.

I also feel, which relates to what Professor Montagnier said a moment ago, to look more carefully in cancers where we know already since a long time that genetic modifications play a major role, because there’s no infections linked to cancer at this moment without additional genetic modifications in the host cell, that’s an interplay between the infections and modifications of the host cell genome. For those reasons I personally also suspect that cancer of the colon is interesting and looking for it for quite a number of variety, in fact I will allude to this in my Nobel Lecture a little bit, and I think it’s still an open question to which extent that it affects a link to human cancer. If you look at it globally and if you include the old /- – -/ cancers right now identified besides Helicobacter pylori in gastric cancer also 10% of gastric cancers are linked to /- – -/ bowel infections you come up to a figure of about 20-21% of the global cancer incidents. I personally believe that this is not the end of the story, and that we are still in for further surprises.

Françoise Barré-Sinoussi: I totally share with what has been said and we have already a lot of viruses that are related to cancer and we will discover more in the future. I just would like maybe one point that we have to consider with the virus HIV, under treatment. For example there is more and more complications that we could see in HIV patients including cancer, and I personally believe that we have to understand better what’s’ going on, why when a patient restores an immunity that he develops cancer, and probably we will discover also several agents that are responsible for cancer.

Harald zur Hausen: I mean to add one point, if you identify infectious agents of human cancer then of course as Professor Montagnier said before, we have not only a better possibility in prevention but also for therapy because in many of these cancers we can identify exactly the molecules that are responsible for the malignant growths. In cervical cancer for instance, if you switch off the two viral genes which are active the cells revert to a quasi-normal state, and so these are, you identify targets and you can much better cope with those types of diseases in the end if you try to develop a targeted chemotherapy in those cases.

You mentioned the search for infective agents, is there a sufficiently good apparatus in place do you think to search for the agents?

Harald zur Hausen: In my opinion it’s an underdeveloped area in the research on the whole, I mean globally, because there are a couple of laboratories working on these questions, but on the whole the interest decreased rapidly in the 1970s, between 1970s and 80s, with the discovery of onco-genes and tumour suppressor genes, because at that time quite a number of scientists believed there was no need any more for infectious agents. You could explain cancer quite readily by a failing interplay between oncogenes and chemo suppressive genes, but that story turns out to be not as simple as it was thought during this period, and many of the former virologists turned into cell biologists during this period. I think it’s a gradually now an awakening interest again in these questions and I hope it will go on in the future.

Luc Montagnier: Yes, we have a much better technology now to identify new agents than we had in the 80s, much more powerful.

Françoise Barré-Sinoussi: We will probably learn from the genomics I think, the new technology will be very helpful to discover new agents responsible for disease.

Luc Montagnier: We don’t intercultivate viruses anymore, it’s /- – -/ in the case, because we can cultivate the papilloma viruses in vitro but all the /- – -/ techniques you can …

Harald zur Hausen: Without molecular biology we wouldn’t have been able to identify the HIVs /- – -/ than without techniques.

So as some last thoughts, what advice would you offer to young people who want to come into the area and search for causative agents for these diseases?

Luc Montagnier: The very first to say there are still plenty of things to find, new /- – -/ objects, which already exist, we don’t know. Actually probably some people say we know only 10% of the virus world, and so there are many other viruses to come, new epidemics perhaps but also plenty of work to do, and probably quicker, in a much quicker than we did in the past. I think it’s a very interesting field, and also for helping humankind because cancer is the main cause of death and disease and it’s a very terrible disease and we have to find all the agents including viruses and microbes.

Harald zur Hausen: If you ask me, I will say develop original and slightly unorthodox ideas, avoid to believe too much in dogmas, and be persistent, and either prove or disprove your own hypothesis.

Françoise Barré-Sinoussi: I totally agree, about dogma, and be very persistent, but also don’t be afraid to work in multi-disciplinary approaches, this is a road for success indeed.

Splendid, wonderful advice, thank you very much indeed, and I hope you all have a most excellent week here in Stockholm and thank you for speaking to us.

Françoise Barré-Sinoussi: Thank you.

Harald zur Hausen: Thank you very much.

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