Françoise  Barré-Sinoussi (2014) - On The Road Toward an HIV Cure

Thank you very much, Stefan. It's my real pleasure to start this morning session and to be here for my second time in Lindau. It's really a wonderful meeting, and I hope that all of you really will enjoy this week in Lindau. So today I decided to talk about not only my work, but the work of many people in the world trying to find a cure for HIV. It's not an easy task as you can imagine. So my first slide is just to remind you that indeed it’s more than 30 years of HIV science today. The virus was isolated at the Pasteur Institute in 1983, and you can see on this slide certainly not all the achievements that have been done over the 30 years. But, I like to show on this slide main progresses that have been done in basic research and in parallel the translation, let’s say, of this basis knowledge in tools for the benefit of patients. So in blue on this slide to be short you have the progresses that have been made in our basic knowledge on HIV. In green you have the tools that derived from those progresses. And in pink you have some success in prevention. Of course as you know we still do not have a vaccine and as you know we do not have a cure. However, we have because of our knowledge on HIV it has been able to develop a therapeutic strategy which is combined antiretroviral treatment which is capable to stop HIV replication in the infected patients. This treatment is also capable to restore at least partially immune function and at the end is capable to prevent the development of the disease AIDS. It has improved the quality of life, it prolongs the life expectancy. Even we can say today that if the treatment is started very early on, the life expectancy is almost the same as one of people that are not infected by HIV. We learnt all over the last years that the treatment is also prevention. It's capable to prevent the transmission of HIV from one infected individual on treatment to his or her partner. It has been a wonderful progress also in the access to the combined antiretroviral therapy in low and middle-income countries. This slide is reminding you that we have about 35 million people living with HIV, most of them are in sub-Saharan Africa. Fortunately this treatment, and really thanks to antiretroviral treatment, more than 4 million of deaths have been avoided. We have today around 10 million of people on treatment. This is not sufficient. As indicated on this slide, the last WHO guideline, published last year in July 2013, indicates that we have to treat earlier, that means we have around 26 million of people in need of treatment. This is a big challenge as you can imagine. So today we can say that in the field of HIV AIDS one of the first priorities is implementation: Implementation of tools to prevent new infection in uninfected people, of course using all the tools – combining the tools like education, condoms, circumcision, risk reduction, antiretroviral treatment -used as prevention today. We have also to improve testing, treating and retaining the patient into the treatment, the continuum of care. Unfortunately the cascade of continuum of care is indicating that the patients on long-term do not adhere to treatment. There is a loss. So it’s a loss which, according to the country, can be 25% to 50%. In addition we have between 30 and 50% of people that do not know that they are HIV positive - this is not acceptable today. So this is a real challenge. Among the challenges that are listed on this list you have the political willingness fighting against stigma and discrimination, which is very important if we want to improve the frequency of people going for the test. We have also key scientific challenges and priorities in HIV science today. I mentioned the biggest one, HIV discovery, of course. We are making significant progress in the field of HIV vaccine during the last years, in particular with the discovery of very potent broadly neutralising antibody, but we are not there yet. I mentioned comorbidity on long life treatment, because unfortunately long-term we can see between 8 to 15% of patients on treatments that develop what we call non-AIDS-related morbidities. And I will make a link by the way towards this challenge to the cure discovery itself. HIV cure is a very big challenge. We have a persistent infection on HAART and we have to understand how to manage to eliminate the virus, to eradicate the virus from the body. So for this challenge we need novel ideas; we need multidisciplinary collaboration; we need to have a partnership between the public and private sector; we need to have international collaboration and of course we need funding. Why do we need a cure? My first answer to that is generally because the patients are looking for it. My first thing when I met them in different countries in the world including in resource-limited settings as yet I always ask the question, “What are you expecting from us as scientists? in 80% of the cases they answer, they would like a treatment that we can stop. So that's as yet. That’s as yet, and this is exactly what Fred Verdult, a representative of people living with HIV, said to my colleague Steve Deeks in in St. Maarten in 2011. Saying to him, “Look I made a little survey in my country in Netherlands and found out that 72% of the people living with HIV are thinking it is very important for them to be cured.” And for reasons that are not exactly the same that Steve Deeks and many others were expecting, for example for them it was very important because they will not have to deal anymore with stigma; they will not be afraid anymore to infect other people. So we have to take this as a scientist into consideration. Why do we need a cure? It's because a lifelong treatment for all is unlikely to be sustainable. Of course we are all calling for universal access to antiretroviral treatment, however as I said only 10 million are on treatment today. For each 3 patients starting treatment we have 5 new cases of infection. We have only very few countries with the coverage of more than 80%. This lifelong treatment, as I mentioned, is with a difficult adherence; we have substantial stigma and discrimination fears; life expectancy is still reduced in a significant proportion of patients; and it’s a long-term cost. So we really need to think about other strategies. First of all we have to understand why - why the infection is persisting on HAART. This slide is showing you that the results, by way of different studies, trying to interrupt the treatment. And we were surprised in those studies to see a viral rebound as indicated on this slide. By looking more carefully, even if the patients who were on HAART had undetectable viral load measure by quantifying the viral RNA in the plasma, it turns out that we were able to detect HIV DNA in patient cells. So this is what we call the reservoirs. The reservoirs are the latently infected T cells. But we have also to consider that even on treatment we cannot exclude a residual low level of residual viral replication, which is related to inflammation, immune activation that remains abnormal in patients on HAART. We have to consider that latently infected cells are present in several compartments, including in the brain. We have to consider also the fact that the treatment not always penetrates very well in all of the tissues of the host. Why is it time to accelerate HIV cure research now? It's because also we have a better knowledge on HIV pathogenesis. I will not go into detail of this slide, but we certainly learned a lot over the years regarding the importance of immune activation, the importance of the persistence of infection. We know that very early on, as this slide is showing you, we have a loss of gut integrity and microbial translocations that probably play a role in abnormal immune activation and inflammation. We know that everything in this disease is decided very early on during the acute phase of infection, and the establishment of viral persistence and viral reservoir is really during this very early phase of infection. Abnormal inflammation is also starting during the early phase and infection is maintained, and both of them are interdependent. Why is it time to accelerate HIV cure research? It is also because we have a better knowledge on the molecular mechanism of HIV latency. This slide is a summary of the different mechanisms that should be considered for HIV latency, first of all as a sequestration of transcription factors but also as potential mechanism of latency. We have to consider the promoter occlusion, the convergent transcription, the defective transcription elongation factors, DNA methylation and chromatin silencing. All these mechanisms are certainly to be considered for the development of novel strategies for the future, but I must say we are still far to understand deeply all the mechanisms of latency and there is progress to be made in this area. We have a better knowledge on HIV reservoirs, which are indeed in many cell subsets and tissues. We know that the persistence and the stability of the reservoir is very long, since even after 10 years of HAART we can detect this reservoir. It was our belief that the CD4 cells that are latently infected by the virus were quite rare. The estimate was between 1/10^5 to 1/10^6 resting CD4 T cells. The very recent data indicates that indeed it's probably underestimated and we have probably more reservoir cells than we thought. What are the reservoir cells? The main reservoir is the resting central and transitional CD4 memory T cells. We have to consider the fact that the latent infection is also present in other cells like astrocytes, monocytes, myeloid lineage, hematopoietic progenitor cells as well. The compartments that contain the latently infected cells are not only the blood but the gut and genital tract, lymphoid tissue, the central nervous system. We are understanding also more and more about why the latently infected cells are persisting. We know that the cells by themselves, the CD4 cells are the long half-life CD4 cells that survive. We know today that there is a homeostatic proliferation of those cells. I explain why: we have the persistence of these latently infected cells. We have to consider immune mechanisms that maintain cells in the resting state, like for example an up-regulation of PD-1 which may contribute to HIV persistence. We are understanding also better and better the main driver of inflammation and chronic activation. I already mentioned microbial translocation but you can see on this slide that there are many other mechanisms like the altered balance of the CD4 T cells subset between T-regulatory T cell and Th17 for example; the loss of regulatory T cells; the role of viral protein like Nef, Tat or Vpx for example. The fact that other pathogens might play a role in this inflammation, like for example CMV coinfection. And this inflammation and activation is probably related to the comorbidities and ageing that we could see long-term in patients on HAART. Which kind of cure are we looking for? Generally when we are speaking about cure, we are speaking about eradication; eradication that means sterilising cure. So that means elimination of all latently infected cells. This is an almost impossible mission after what I said. However, we have one proof of concept: the Berlin patient who received a very complicated treatment bone marrow transplant from a particular donor with a mutation in the co-receptor CCF5 mutation which is present only in Caucasians. So it's not a strategy that can be used at large scale, but we cannot detect anymore the virus in different compartments of his body. Remission. Remission is probably our main goal, and it's more reasonable in my opinion. Remission that means that we will have a long-term health without any treatment, without any risk to transmit to others. And we have also proofs of concept. What are the proofs of concept? One of the first ones by the way, our natural protection against AIDS in African monkeys that do not develop AIDS as they have viral replication. They have attenuated inflammation, attenuated chronic immune activation. Bone marrow transplantation I already mentioned, the Berlin patient. We thought we will have 2 other cases with the Boston patients who received also a bone marrow transplant, however, we learnt after they stopped the treatment that unfortunately they had a relapse of HIV viremia We have HIV controllers, the people that are naturally controlling their infection: they never receive antiretroviral treatment; they have undetectable viral load, low size of reservoir; they have a very efficient suppressive CD8 response, correlated to HLA B27 and B57, so to a particular genetic background. They have also for some of them a capacity to restrict the infection of their CD4 cells and of their macrophages. Finally we have also the case of "functional" cure in very early treatment, the "Mississippi baby", probably you have heard of her from the media, she was treated 30 hours after birth, so very early on, for 18 months. Her mother stopped the treatment for 6 months, she came back and the virus was not detected anymore in the baby. In my country, in France, we, my group in collaboration with others, we identified a group of 14 patients, we have 20 patients today, treated very early on about 10 weeks during the primary infection for 3 years. They stopped the treatment. Now it's 9 years that they are without any treatment, they are doing perfectly well: They have low size of reservoir as well; they don’t have a strong CD8 suppressive response; they don’t have the same genetic background as the HIV controllers So we are trying to understand why - why these men were capable to control their infection. So that's the reason, we thought it was time at the International AIDS Society to accelerate research on HIV cure. I personally thought that the best way to go was to have a bottom-up approach and to really ask a group of scientists to work together and to define what are the main priorities to accelerate research on HIV cure. It's what we did, and we published in 2012, in Nature Review Immunology, a kind of scientific roadmap with the main priority in cure research. We can summarise them as 7 priorities which are shown on this slide: Starting from molecular and cellular and viral mechanisms of persistence that still need to be better understood; have a better understanding of tissue and cellular sources of persistent infection in animal models as well as in patients on long-term ART; to understand better the origins of immune activation and dysfunction in the presence of ART; to understand better the host and immune mechanisms that control HIV infection but still allow viral persistence; to have better assays to study and measure the reservoir; and to develop therapeutic strategies and immunological strategies to eliminate the latently infected cells in patients; and also to certainly enhance the host response to control replication. Where are we today? Can we cure HIV latency with "reactivation" drugs? Several drugs which are mentioned on this slide like NF-kappaB activators have been tried already. And the administration of the Vorinostat in a patient on HAART showed that we can reactivate the virus but indeed, when we measured recently, the size of the reservoir is the same. So it’s a little bit disappointing, I must say. So it's probably not enough. We need to ask the question: What proportion of the reservoir is susceptible to this drug? Are proteins of variants being produced on this kind of treatment? How safe is this approach? Can we cure HIV infection with immune-based therapy? We have some arguments to think that that might be the way to go. For example we know that the frequency of HIV DNA-containing resting memory cells correlates with the frequency of activated CD4 T cells. By the way we know in our patients that were treated earlier, the VISCONTI patients, that they have a very, very low level of inflammation and immune activation. We have this study with rapamycin, which reduces CCR5 expression and T cell activation and was associated with the lower size reservoir in post-renal transplant. So we have several questions that we are asking regarding immune-based therapy today. Can we enhance killing of HIV-infected cells by vaccine therapy in vivo? There is promising data like this study of Louis Picker in a macaque model, using a very highly pathogenic SIV and using as a vaccine CMV vector which is capable to induce a very high level of effector CD8 T cells in lymphoid and mucosa tissue and this study clearly showed that the CD8 response was capable to decrease the size of the reservoir in the monkey. So this is very promising. Probably... I'd like to say that regarding vaccine therapy: we have to consider also the antibodies. There is very promising data today with broadly neutralising antibodies, and I must say that the data also in macaques is very encouraging regarding the possibility from broadly neutralising antibodies to decreasing the size of the reservoirs. Finally can we cure HIV infection with allogeneic stem cell transplantation? I told you about the Boston patient - there are those gene therapies studies using for example CCR5-modified T cells that show some interesting data. But my question is whether gene modification of T cells for a cure is feasible? Can stem cells be harvested gene-modified and transplanted in a safe, effective, affordable, and scalable manner, especially in resource-limited settings? What are the barriers but new opportunities? We are very... there are new opportunities for clinical research toward a cure. I already mentioned some of them like the direct acting anti-latency drugs, anti-inflammatory drugs But we have to keep in mind that we really want a strategy that will be affordable as I say for resource-limited settings. The future cure strategy will probably be a combined approach with these different strategies I would like to say based certainly on our basic knowledge on the mechanism of persistence. Quantifying the reservoir and tools for cure studies are really something that we have to work on. I told you the Boston patient really said to us, you don’t have the right to measure the reservoirs. We need to understand the biology of HIV persistence as well for that. We need to have a biomarker to predict the efficacy of the functional cure. We need to have those markers to evaluate the impact of any intervention on the reservoirs. And based on those biomarkers, in the future, I would not be surprised to have an approach, let's say, towards a personalised cure therapy. So I will end by saying that what we need is really an integrated strategy with all the components Remember inflammation, as it was said yesterday, inflammation is critical in many diseases We have to work also with social scientists and scientists involved in economic science. We have to work together with the stakeholders, with the donors; and it's what we did at International Society by implementing an international Advisory Board responsible for implementing and following the strategy: to make funding, of course; to have a coordination in funding; and to make sure that we have international multidisciplinary collaboration at all the levels. I'd like to say that we might be successful, I'm sure we will be successful in a remission, in a chemical remission in the future, if we work all together as we did in the very early years of HIV research. It's what we are trying to do with my co-chair of the next conference in Melbourne, Sharon Lewin. I was glad to see in Lindau the strong implication of Australia. Sharon is from Melbourne, she will be as the Director of the Peter Doherty Institute in Melbourne. And I am pleased to say that we are used, with Sharon and Steve, to organise regularly now a meeting on HIV cure before the AIDS conference. Thank you very much for your attention.

Françoise Barré-Sinoussi (2014)

On The Road Toward an HIV Cure

Françoise Barré-Sinoussi (2014)

On The Road Toward an HIV Cure

Abstract

Since the first cases of AIDS in 1981 and the identification of its etiological agent in 1983, much progress has been made in both the development of tools to prevent and treat HIV infection and the access to these tools. In particular, the wide array of antiretroviral treatments that now exists has considerably transformed the face of the infection from a lethal disease to a chronic condition. Today, thanks to unprecedented international efforts, the more than 10s of millions of people living with HIV have access to these life-saving treatments in resource-limited countries.
However, the sustainability of these life-long therapies is a real challenge both for the patients who have to meticulously take them each day and for the global economy considering their cost. Indeed, these antiretroviral treatments are not curative as HIV latently persists in reservoir cells and in many compartments of the host.
Novel therapeutic strategies that would cure HIV infection or at least induce a sustainable remission in patients without the need to further take medication are thus an absolute necessity. The increased knowledge of HIV reservoirs and of the mechanisms of persistence as well as reports of proof of concept studies, have generated great optimism in the scientific community, which now believe that sustainable remission of HIV infection is an achievable goal.
In 2010, the International AIDS Society launched the “Towards an HIV Cure” initiative with the aim to mobilize the scientific community and accelerate research on this topic, which has since then become a priority in the HIV science agenda.


RECOMMENDED READINGS

1. Towards an HIV cure: a global scientific strategy.
International AIDS Society Scientific Working Group on HIV Cure, Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O'Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Van Lint C, Verdin E, Woolfrey A, Zaia J, Barré-Sinoussi F.
Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the recommendations of the group to funding agencies and to the international community.
Nat Rev Immunol. 2012 Jul 20;12(8):607-14.

2. HIV cure research: Advances and prospects.
Passaes CP, Sáez-Cirión A.

Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease in patients on cART. However, in spite of this favorable outcome, cART is not curative and patients are at risk of developing non-AIDS malignancies. Moreover, universal access to cART is still restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
Virology. 2014 Apr; 454-455C:340-352.

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