Françoise  Barré-Sinoussi (2010) - HIV, a Discovery Highlighting the Global Benefit of Translational Research

Thank you very much for these very nice words of introduction. What I’d like to do in the next 20 minutes or so, it’s a short talk so I’m not going to go into details but I like to give the example of HIV to show the young researcher how it’s important to make multidisciplinary and translational research. For HIV everything started really by observation, observation of our colleagues, epidemiologists and clinicians who reported the few cases of young homosexuals that were all presenting with severe immune deficiency. It is also based on those observations that we had the idea that probably a virus was the cause of this newly recognised epidemic. First cases were found in haemophilic patients indicating that probably a virus was the cause of this new emerging disease. And it is by our colleagues, the clinicians that we have been mobilised at the Pasteur Institute. They came to us because some of them were following training and virology course at the Pasteur Institute and they remember that Luc Montagnier and Chermann and myself were giving courses on retroviruses. So this story really started like a good opportunity at the point that it was an evolution of technology and evolution of research on retroviruses, everything start from opportunities and to be there at the right moment with the good technology. They recognise in France the first cases of AIDS in 1982, but at that time the first human retrovirus was identified in the United States by Robert Gallo’s group and these human retroviruses was causing T cell leukaemia. The virus was infecting T cells so our colleagues and clinicians came to us at Pasteur and asked whether we thought that HTLV could be the cause of AIDS. And our first reaction if I remember correctly was to say this is curious because HTLV is transforming the T lymphocyte. And you are just explaining to us that the cells are dying in the patient. So to remember that in other retroviruses like for example feline leukaemia virus, the cats were dying of immune deficiency before dying of leukaemia. Progress in technology turn out that few years before it was also the identification of what was called T cell growth factor, now known under the name of interleukin 2, that means we were able to grow in the laboratory T lymphocyte using these cellular factors. So it's really this collective adventure started in the early ‘80’s ... the clinician and we had a very decisive meeting at the Pasteur Institute when we had very simple question when, where and how to look for which virus. I’m showing you this slide for the young researchers, it’s also to keep in mind that we have to be careful about dogma. If we had started with the idea that HTLV could be the cause of the disease certainly the approach that we have used will not have been successful. So it’s how the virus was identified in 1983, it was called at that time lymphadenopathy-associated virus because where we decide to look for the virus was in the lymph node of the patients. And another important decision was to decide to follow in the culture of the cell derived from the left node, to follow in the culture every 3, 4 days in culture to find out a reverse transitive activity with the enzyme which is specific of this family of retroviruses. And that was also an important decision, when to look. A few days after the culture we had the first sign of disease virus in our supernatant. So immediately after this first identification of the virus we of course had in mind to go to application as fast as possible. First of all we had an emergency, the emergency was to prevent blood transmission and transmission of HIV, this new virus in haemophiliacs. So that means that we had to develop diagnoses tests and that was done very rapidly and in parallel these tests were used to make very large epidemiological survey in order to make the link between the virus and the disease itself. Of course, these diagnoses tests were available to test, to prevent mother-to-child transmission and through information, counselling and so on, to try also to have some impact on the prevention of sexual transmission. We’re rapidly after the isolation of the virus, also we together, we mobilised our colleagues immunologists to work with us and to try to identify the tropism of the virus and we very rapidly showed that the virus was infecting preferential ECD4 lymphocyte, but also that the CD4 molecule itself was a receptor of the virus, that was the basis of monitoring CD4 cells in the patients, and it’s still in use today. We started very rapidly, after mobilisation of our colleagues and molecular biologists at Pasteur to characterise HIV genome and to start to characterise a repetition cycle of the virus into target cells. With another colleague we start to characterise a reverse phosphatase of the virus with the idea that individuals of the reverse phosphatase maybe important to develop therapies. Indeed, the first antiretroviral drug that has been shown with some efficiency was AZT, AZT was not sufficient as a therapy, but AZT was the first drug showing that we can prevent mother-to-child transmission. And you just heard from Professor Montagnier that today, since 1996, we have a very efficient combined 3 therapy, also named as highly active antiretroviral therapy. We characterise the genome of the virus and very rapidly we found out that it was a very complex organisation. You just saw on the slide of Professor Montagnier, the organisation of the virus and very rapidly, as soon as 1984, we knew that we had a very viable virus. But the identification of the genome of HIV was certainly the basis to develop later on a monitoring test for measuring the viral load in the patient and also to follow resistance to antiretroviral treatment as well. Since then, since the beginning of 1983 it has been a lot of progress of course in acknowledge and in changing biology and pathogenesis, I am not going into the detail of all this progress that are reported on this slide, I just let you know that of course we know that HIV originated from a transmission of the virus from monkey to humans although the intermissions were very rare. And of course we have made a lot of progress in our knowledge of the interaction of the virus and the host and leading to the development of progress in the knowledge of disease outcome. It has been a lot of progress in diagnoses and therapy but as you know regarding the vaccine it has not been very successful. Vaccine research started as soon as 1985/86 and still today we don’t have any efficient vaccine. Another discovery at least for me was the fact that we will have to face a global scale epidemic. And I had the chance personally to go as soon as 1985 in Central African Republic and to realise the situation over there in those countries. So the theory started from the discovery of the disease in the United States in 1981, followed by the discovery of the virus in France, but indeed we have to face a global epidemic and we had really to learn how to work all together. I mentioned Central African Republic, but soon after in 1988 I also started to go in South East Asia and it was there before the identification of the first case of HIV in Vietnam in 1990. So it’s how really another story start, the story how much is important and it’s our responsibility as a scientist to provide scientific evidences to convince the political leaders and authorities to make intervention in their countries. It’s important for providing scientific evidences to make multidisciplinary research and to work also together with HIV communities, their participation I think is an example in the field of HIV. We have learned to work altogether, scientists, doctors and activists. In the developing world it’s very important to provide scientific evidences directly on site and to make multidisciplinary research directly on site to provide this scientific evidence locally in order to develop intervention through convincing the political leaders. So as I heard yesterday students and young researchers are asking when they are from poor resource limited countries, whether they can provide contribution, of course they can contribute and they will contribute and there is a lot of progress regarding science in resource limited countries in the field of HIV, I’m sure in other fields. Those contribution from the country itself are very important for the decision, for the benefit of the public health in their own country. Regarding HIV it has been progressive to access antiretroviral treatment in those resource limited countries. This is a report of UNAIDS WHO last year, in 2009 showing that we improve the access of treatment by 10 between the end of 2003 and the end of 2008 as you can see on this slide. That means that around 40% of patients that are in need for antiretroviral treatment are treated. This is bad and previous WHO recommendation to treat patients when they are 200 CD4 cells or less. We know today that the recommendation is to treat patients when there are more CD4 cells. So that means that all therefore that has been done its already wonderful but its not sufficient at all. We know today that for 2 patients starting treatment there is 5 new cases of infection and still there is 2.7 million new cases of infection per year. Today we have more about 30 million of people living with HIV all over the world and still 2.5 million of deaths per year. So the effort should continue, the effort should continue, in particular we need to have future strategy to reduce the incidence of HIV-1 globally in the world. And of course it will be combined approaches. One approach is based on behavioural changes, and for that information, education is very important, of course. And as researcher we have to participate to this information education program as well. We have biomedical strategies like condoms use, like circumcision that was proved to reduce the incidence, the risk of infection by 50/60% and we have the antiretroviral treatment. We have that already showing that treatment as prevention is a nice approach to reduce the risk of infection, that are indicating that around 90% reduction of the risk of transmitting the virus when someone is on treatment. One also, part of the approach to reduce the incidence of infection is certainly to improve everywhere in the world social justice and respect of human rights because if we want to treat earlier we need to improve testing. And to improve testing we have to fight against discrimination and stigmatisation of patients that are HIV positive. Because this is one very important obstacle today for someone to go for the test is afraid about the eyes of the others. So this is a combination of those approach, broad based and biochemical approach and those other issues that we need to work for the future. Of course another component for the strategy will be the vaccine. But still today we don’t have it. So we need to think about the new therapeutic prevention strategy for tomorrow. On that slide you have 2 pictures, the picture of the situation, to be brief I mention the north, today we are not speaking any more about AIDS mortality, we are speaking about chronic HIV infection, patients are living with HIV. In the poor countries still we have AIDS mortality, you can see on this slide that in our countries in Europe, United States, after 5 years after infection the mortality rate is indeed exactly the same in the general population as in patients infected. In other countries still we have 8 to 26% of patient mortality during the first year of treatment initiation even. So that means that we have to improve the access of treatment as I said, we have to improve also the access of pregnant women to antiretroviral treatment, only 45% of them have access to treatment. But we have also on this slide some other challenges that we have to face for the future. Professor Montagnier just mentioned the viral latency in HIV reservoir, this is one critical issue because we cannot stop the treatment and we have to have new therapeutic approach at least to reduce the size of the reservoir in the future. Another critical issue in HIV research is to understand better the mechanism by which the virus or viral component are inducing very rapidly inflammation activation and we know that there is insufficient immune restoration even on antiretroviral treatment. We have in our countries, in Europe and United States new complication, new complication associated to long term HAART, for example you can see on this slide that 8% of patients that are on long term HAART are developing cardiovascular disease. Some of them are developing cancers as mentioned before, lymphoma mostly but other cancer as well, 15% of them. Some of them are developing liver disease, around 7% and we are seeing more and more neurological disorders in HIV patient on long term HAART, aging disease, osteoporosis, Alzheimer like disease. So we have to improve the situation regarding, acknowledge also why, why there is such complication, what is the role of the virus or viral component, what is the role of HAART together with viral components. So we still need further research today. We certainly have learned as I said before from HIV pathogenesis but we need to learn much more, much more in particular during this very early phase of infection which is in grey on my slide. As you can see during the very first, lets say week, I was ready to say first hours after infection. We have already data indicating that everything is decided, during let’s say the first 96 hours after exposure to the virus. When I say everything is decided in the HIV infection outcome, that means that very rapidly after exposure to the virus you have the infection itself, the dissemination of the virus in the body and the establishment as you can see on the red part in the bottom of the slide, the establishment of HIV latency and HIV reservoir. We have also to learn better what are the mechanics, like to explain the chronic immune activation and how to control chronic immune activation, how to control the establishment of the reservoir. We know all of us here that we have a very complex interplay between the virus, viral components and the host itself, of course we have learned about HIV diversity, we know about the tropism of the virus, and variation in the tropism of the virus and the capacity of the virus and also we know that some of the variation are due to the virus, some of the variation are due also to host cell factors, involving in virus life cycle. We know that the cells have intrinsic cellular defence with restriction factors. It has been discovered like APOBEC TRIM5 and Tetherin, the last one. And we know also that the virus and components of the virus have immune suppressive capacity, they’re capable to induce abnormal activation signal. Some of the viral components that are capable to induce abnormalities are the envelope, the nef protein, vpr and so on. And of course they will influence the immune response, the alternating immune response as well as the adaptive immunity. And of course the genetic of the host is important for the host immune response as well. So we have to consider both the genetic diversity of the host and the genetic diversity of the virus itself. There is distinct, innate and inflammatory response to HIV, SIV infection in the host and we know that indeed this distinct responses is depending of the dialogue, the dialogue between different actors of our immune defence. We have to consider the plasmacytoid dendritic cells, you know that are defence, several actors are playing a key role, like the plasmacytoid dendritic cells, like natural killer cells, T-cells and so on, of course B-cells for the production of antibodies. But you have to consider that the virus is coming, HIV and viral protein that recognise, that can be recognised by plasmacytoid dendritic cells. But the response of the plasmacytoid dendritic cells through receptors, receptors like TLR’s but even maybe through other receptors for example a paper will come soon showing that one restriction factor TRIM5alpha might be one receptor. So we have to consider the interaction between receptors and ligands. And according to the diversity of both the receptor and the ligands you may have diverse innate response. Innate response involving pDC’s, NK cells and of course involving as a consequence different recruitment that activation of those cells, that are critical for B-cells and T-cell response in lymph node tissue, like lymph node as shown on this slide. But we have to consider the diversity as I said to the host receptors or ligands. Like for example the NK receptors which are important, the KIR , we know the genetic polymorphism of the KIR is influencing HIV infection. We know that HLADR is influencing of course HIV infection and we know that nef is down regulating HLA, class 1 molecules. So we have to take together both the host and the virus diversity in the distinct innate and inflammatory response that makes then distinct HIV, SIV disease outcome. And we can learn from this diverse spectrum of response. Indeed it is different models that can be used to try to understand better the protection against HIV or against AIDS, let’s show very rapidly on this slide 2 of the model on which we are working in my lab and others are working as well. We have first HIV controllers or SIV controllers in the monkeys. Those are very interesting because they control naturally the reservoir, they have low level of reservoir. And no detection of viral load in the monkey, natural control of the repetition of the virus. The other model is the African primate, that are infected by SIV, 40/50% of them in Africa but they do not develop the disease, why, because they do not have abnormal immune activation of the immune system, do not have abnormal inflammation. So we can understand from both model and we are starting to understand from both model. For example HIV controllers, we know already that they are, most of them are HLA, B57, B27, we know that about half of them have very strong CD8 response but so 50% of them we cannot explain by a strong CD8 response but maybe by innate immunity or viral components. And also we are learning from the monkey. So to finish I would say that we are learning on HIV, but I am convinced and I like to believe that we can learn beyond HIV AIDS, HIV is a retrovirus and I just mentioned that of course we have new challenges with cancer, with aging disorders and HIV disease. We know that retrovirus in animals, we were very much studying at the end of the ‘60’s as potential agent for causing cancer and leukaemia. But today HIV might be also a tool to understand better cancer and lymphoma. HIV may also be a tool to understand better aging disorder, HIV may certainly be a tool to understand better immune defect and inflammatory and autoimmune malignancy. And the last slide says that HIV AIDS since the beginning has been a wonderful scientific and human adventure but it’s still continuing. We have new challenges, new technology, new concept to say and a new generation of players. They will be responsible for the new discovery but they would have to keep in mind, they have to work with connection, connection with others as shown on my slide, basic science together with clinical and operational research, basis science and different discipline and also one discipline that I mention on my slide which is not represented at Lindau is a social economy called science which is an important part also. And to work together, all together with the patients themselves. Thank you very much.

Françoise Barré-Sinoussi (2010)

HIV, a Discovery Highlighting the Global Benefit of Translational Research

Françoise Barré-Sinoussi (2010)

HIV, a Discovery Highlighting the Global Benefit of Translational Research

Abstract

The fantastic progress made in medicine led the scientific community to hope about the complete eradication of infectious diseases in the middle of the 20th century. The sudden emergence of AIDS in the early 80’s cruelly reminded us that this dream was far from being true.

In June 1981, clinicians in the United States first reported few cases of Pneumocystis carinii in homosexual men presenting all a severe immune deficiency. Soon after, similar observations were made in France. Realizing the urgency, some French clinicians started a working group and contacted, in December 1982, retrovirologists at the Institut Pasteur. The discovery of HIV few months later originated from this collective adventure, which mobilized clinicians, researchers and patients altogether. This collaboration later proved crucial to rapidly expand our knowledge of the virus and developing the first diagnostic tests and antiretroviral therapy (ART).

Since then, the continuous mobilization of the scientific, clinical and patient communities, supported by local authorities and international organizations, enabled substantial progress in the worldwide fight against AIDS, especially in the field of access to ART in resource-limited settings. But beyond HIV/AIDS, these efforts prompted a global improvement of health care systems for the benefit of all patients independently of the infection they are suffering from.

More than 25 years after the discovery of the etiological agent responsible for AIDS, research priorities still remain care, treatment and prevention with the major objective of developing a preventive vaccine. This objective remains distant today and in order to reach it, we must pursue our work following Pasteur’s vision of scientific commitment: a multidisciplinary and translational research for the global benefit of humanity.

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