 Thank you very much and welcome to everybody. I'm pleased to introduce this session. We will have several speakers, and I will introduce each of the speakers very shortly. The first one will be my co-chair of the conference, Sharon Lewin. Sharon, as you know, is Director of the Infectious Disease Unit at the Alfred Hospital, and she is Professor of Medicine also at the University. I have the pleasure indeed to co-chair not only the conference with Sharon, but we are also co-chairing a symposium on HIV cure together with Steve Deeks, and myself together with the help of Sharon are also now co-chairing the IAS towards an HIV cure initiative. So the second speaker after Sharon will be Deborah Purso. Deborah Purso is very much involved in the work on the so-called Mississippi baby, who is not a baby anymore. By the way, Deborah will tell us about the latest news regarding the Mississippi baby. The next speaker will be Dan Baruch. Dan is Professor of Medicine at Harvard Medical School, and Dan is working on a new vaccine approach, in particular using a broadly neutralizing antibodies and he will tell us about the last latest data regarding the use of broadly neutralizing antibody in cure. The next speaker will be Ole Sogaard, working at Harris University in the Department of Infectious Disease of the University. Ole will present the latest data that we have using a drug, a medicine, a drug which is able to reactivate the latently infected cells. The next speaker will be Nicolas Chamon. Nicolas is currently working at the Vaccine and Gene Therapy Institute in Florida. Nicolas will present work that has been presented yesterday at the Cure Symposium regarding new assets to quantify and to measure the reservoir. Steve Deeks at the end will tell us about his own vision of the future of Cure. So please, Sharon, first. Thank you, Francoise. So I thought I'd set the scene of where Cure Research has come to, especially given what we've found in the last year, and this builds on a workshop that Francoise mentioned of over 250 participants we had over the weekend here in Melbourne, meaning that we really have the best and brightest Cure Researchers all with us at the moment. And I think there are some big issues that we've learned about. And the first is that we probably are looking at the moment trying to achieve long-term remission when we talk about Cure, meaning time off antiretroviral therapy. How long can we go? And we've realised in the last year that the virus can really hang around for quite some time and then pop up at an unexpected moment in time. It is exactly what we found with the Mississippi baby. What we've learnt from that is that we need much better tools to measure virus while people are on treatment and once they stop treatment. And we need much better assays to really know where that virus is hiding. And that builds that. Nicola Chamour will talk a bit about that. I think the most recent cases of the Mississippi baby and also the Boston patients who also rebounded after stopping treatment, admittedly rebounded late after stopping treatment, also tells us that what we need to do here is not just tackle the virus that persists on treatment but also that we need a good immune response there ready to tackle any virus that emerges. And I think Dan Baruch's work shows us clearly that will help us solve some of those puzzles. Finally, although we know that early treatment most likely significantly reduces the amount of virus that persists in patients on antiretroviral therapy. Most people get treated during chronic established infection and we still need to understand how to eliminate those long lived reservoirs of virus. And at the moment we've talked largely about kick and kill strategies but we probably need to develop other approaches to those long lived reservoirs. And finally, you know, 80% of people living with HIV of course live in low income countries. There's a lot of effort now to try and engage low income countries in the search for a cure as well as greater engagement of the pharmaceutical industry which although some companies have been actively involved in this area, this should be extended and there are efforts towards that with discussions around perhaps developing a public-private partnership. So with that sort of background I'll hand back to François. Thanks, Sean. So as I said, now Debbie will say a few words about the last latest development regarding the Mississippi entrance. Thank you, François. So I'm here with Dr. Hannah Gay from the University of Mississippi Medical Center. She's sitting in the front row and in the past three weeks we've identified that the Mississippi child now has rebound varemia. This rebounding of virus was detected during a routine clinical monitoring visit where viral loads in CD4 T-cell counts were done. The viral load rebound was confirmed on a repeated test within 72 hours and the child was restarted on antutrile treatment. On antutrile treatment the viral load has dropped and her CD4 counts have increased from 28% back to 42%. Certainly this is sobering news for us because we've never experienced a child who's been HIV infected and have gone off treatment for 27 months without having any detectable virus using our most sensitive assays in the peripheral blood of this child. So what we've learned from this, I think first is and foremost is this child was indeed HIV infected. The effects we saw were really the effects of treatment, not prophylaxis, as has been discussed earlier. The second is we've learned that HIV can establish latency very early. This child is treated at 30 hours of age and that this latent infection can persist for years. The child is almost four years of age and can persist in a quiescent state in the absence of any HIV-specific immune responses. Dr. Luzyaga followed this child immunologically for two years and we have not detected any HIV-specific immune responses. The ultra-sensitive test looking for traces of RNA did not detect any RNA before rebound veremia. So with rebound veremia, the child has seroconverted and is now HIV seropositive and has control of veremia, is on antradural treatment and doing well and will be followed by her pediatrician. So we think we've learned a lot from this case and it does provide us a strong rationale to move forward with the clinical trials to look towards using very early therapy to achieve virologic remission in perinatal HIV infection. Thanks, so Debbie. Dan, please tell us about your work on the vaccine candidate and vaccine also as an approach for cure. Sure, thank you. I'll first discuss a preclinical animal study that has a remarkable parallel to the recent events of the Mississippi baby that Debbie just described, showing that in an animal model, the vial reservoir is also established very early, remarkably early, much earlier than anyone had anticipated before. This manuscript is published today in the journal Nature. In this study in Monkeys, we showed that early antiretroviral therapy, even very early antiretroviral therapy, is not early enough and was insufficient for curing the vial reservoir. It appears that the reservoir is established even prior to the first evidence of plasma viremia, suggesting that if these data are translatable to humans, then as soon as one is able to diagnose a patient with HIV infection, even with the lowest levels of plasma virus, then the reservoir has already been established, a reservoir that is also refractory to antiretroviral therapy. Clearly early antiretroviral therapy has benefits and reduces the vial reservoir, but in the study that we have published today, it was unable to eradicate the reservoir. The implications are that strategies, in addition to early antiretroviral therapy, might be needed for vial eradication and cure. Such strategies include monoclonal antibodies, therapeutic vaccines, as well as direct reservoir activators. And many groups, including ours, are working on all three of those strategies. I think I'll stop there and head over. Thanks, then. Ole, can you tell us about what is an embargo today? Sure. So, as Stan was saying, one of the strategies to maybe try to reduce the reservoir and potentially eliminate the reservoir in chronically infected patients is to use this kick-and-kill approach where you attempt to kick the latent infected cells. So the cells that have archived HIV within their own DNA to kick these cells out of their resting stage and expose the virus on the surface of these cells so they can be killed and eliminated by the immune system. So this kick-and-kill approach, we tried to test in six patients at Orhus University Hospital. We used an H2H, which is a group of anti-cancer drugs. The H2H that we used is called bromidepsin. Bromidepsin has been shown in cell cultures and in cells taken out of patients to be able to activate these latent infected cells. So that was our rationale for moving into a small clinical trial. In this trial, we included six patients, five males, one female. They were all well-suppressed on individual treatment for a duration of, a median duration of nine and a half years. What we saw, we infused bromidepsin three times over the time course of 14 days. What we saw was a significant release of viral particles from latent infected cells into the plasma of these six patients despite their own antiretroviral treatment. So these viral particles were easily detectable with standard clinical assays. So we could detect the viral particles with the same assays that we used to monitor treatment as runs in patients and also an assay that is used by blood banks to screen for HIV in the donor blood. Next, we went on to see if we could at least find a significant reduction in the size of the reservoir in these six patients and from our preliminary analysis, it doesn't look like there's a significant reduction in the size of the reservoir in these six patients. So what this tells us is that we can activate cells, we can induce the release of viral particles into the blood of the patients, but this may not be enough to actually make a difference on the size of the reservoir. So the next step would be to use strategies like H-Dangan heapsis and combine them with interventions that are targeted towards the immune system. So this could be an HIV vaccine and we actually have that study just starting last month, but it could also be other immune interventions that attempts to enhance the immune system's ability to kill these reactivated, latently infected cells. Yeah, I think those. Thank you. Nicolas has been involved since now many years in trying to identify the cells that plays a role of reservoir and now is trying to find new assets to quantify and measure the reservoir, which is critical for the future. Yeah, thank you, François. As you just said, it is actually a scientific priority of the International AIDS Society to develop novel assets to measure the size of the reservoir and it is important because we want to find ways to monitor the efficacy of eradication strategies and right now the assets that we have are pretty expensive, they require a lot of blood and we're not exactly sure what they measure. So we spent a lot of time during the past few years trying to develop novel assets that could be used in those eradication trials and we came up with this new strategy that we called TILDA, T-I-L-D-A, which is a novel asset that requires only 10 milliliters of blood that is relatively inexpensive that can be run in two days and more importantly, that can be implemented pretty much in any lab in the world because you need very basic instrumentation to use this asset. So using this asset, we've been able to confirm the benefit of early antietroval therapy early in infection. So basically we found that the size of the reservoir was much more restricted in people who start out very early on. Of course the next step for us is to use this asset in clinical trials and again to monitor the efficacy. So the value of this HIV cure symposium was to put all of us in the same room and basically I talked with Oli earlier and definitely we will use some of the samples of this clinical trial and run them in the novel asset that we have developed and eventually of course what we want to do is to make this asset available to the scientific community. Thanks, Nicolas, to hand. Steve, your vision. Yes, I've been asked to talk about sort of the future and just make a few quick comments. I think it's quite clear right now that the international community is fully engaged in cure research. The funders are engaged, the foundations are engaged, the communities are engaged, most of the academic groups are engaged. This meaning that we just had was supposed to be for a couple hundred people but we had a very long waiting list so there's a tremendous amount of interest. I will say that though in the future in terms of potential barriers to success the one major group not yet fully engages industry. We're not going to cure anyone unless we develop new drugs and that's what industry does and so there's a lot of efforts by the barriers that are preventing industry from getting engaged and we think we know what they are and we think we might know how to overcome them. Scientifically, I think there are three big issues that we need to tackle. First, where does the virus live? Debbie's case, the Mississippi baby, suggests that a single virus can live in a single cell living in some reservoir, somewhere in the body and that's all it needs for the virus to take off. So we need to figure out exactly which cell the virus is in and where it resides. That's the first thing. Second thing, as Nicola just mentioned we need to be able to measure the virus better. There are probably dozens of cases around the world now in which people have no detectable virus absolutely no detectable virus on therapy and they may not be cured. We need better ways to measure this. And finally, of course most importantly we need to begin to translate pilot studies into real clinical studies to see if we can actually really advance the cure agenda. And I think this meeting is going to be remembered for two things. Number one Olay's data is the first clear evidence at least to me that we can truly identify the latent reservoir, the hidden virus and shock it out of its hiding place and that is absolutely critical. I don't think anyone has shown that before to the same degree that Olay has shown in his study and so I think actually that is the single most important advance of this meeting and it's going to have a huge impact on the future. That's shock. That's getting the virus out of its hiding place. But once it comes out of its hiding place we have to kill it. And I would say actually Dan's data that he presented on these novel antibodies that can potentially do that is also going to have a huge impact on the future. So that's my vision. I think we need to get industry engaged. We need to find out where the virus lives. We need to know how to measure it and we need to begin to do bigger and better studies in terms of shock and kill. Thanks. So now the floor is open for question. Please introduce yourself, give your name and introduce yourself. Julia Medjou from Fairfax Media the age and the Sydney Morning Herald. You mentioned the barriers, knowing the barriers to industry involvement. Can you explain what you think they are? Well, for a company to figure out whether one of their molecules or drugs might actually contribute to a cure we need to be able to do these small studies in which we give the drug to people and show that it does something. So ultimately we need a biomarker. We need a way to quantify the size of the reservoir. We need to be able to go into a person and figure out how much virus is there so that we can give these drugs in 10, 20 people to see if we can reduce it. We don't have that assay yet. So that's the first thing and there's a tremendous amount of effort going on to identify that tool. The second thing is actually a bit more problematic is how are we going to define a cure and how are the regulators, the people who actually approve drugs are going to define a cure. And I think industry needs to know that. They need to know exactly how it is that they're going to get an intervention that is approved and can be commercialized so they can sell it. And right now the field does not have a definition of how we're going to do that and that's a major challenge. Pam Harrison, Medscape over here. Thank you. Dr. Sogorn, Pam Harrison, Medscape. You didn't see a reduction in the size of the reservoir. Was that possible because you weren't using a potent enough antiretroviral therapy to mop up the release of the viral particles that you did activate? That's a good question. So I think for an effective reactivating strategy to be successful, you need some immune cells that are able to recognize the cells that you expose and to kill them. I think this is the major barrier to actually reducing the reservoir when you have a potent reactivating agent. So I think Roman Dabson in this trial was quite convincing in reversing latency at least in some of the cells, but we don't know if we reversed latency in 1% of cells or in 50% of cells. So there's still a lot of work to be done to know how much you can actually, how much reactivation you can induce, but at least this is a step forward in the sense that you can measure it with standard assays and commonly used assays all over the world. Hi, it's Sophie Scott from ABC. Just another question for Ola. So how significant is your research that you're presenting in terms of moving towards an HIV cure? So I'd rather let someone else comment on that. So I think it's significant in the sense that it's something that now can be investigated in settings that don't have that advanced laboratory assay set up so you can use standard assays. So in that sense it's significant, but it's still just another step towards something that may end up being a cure for HIV. So it's a step in the right direction, but I think it's just a step. Can I just follow up? I'll just follow up there. I mean, I think the significance of it is that we have always thought once the virus gets inside a cell and goes to sleep, it's stuck there forever. And what Ola's, the first studies of these drugs showed you could wake it up, but you only found a bit more virus inside the cell. And Ola's study has gone that step further to show you can wake it up and make enough virus to leave the cell. And that's quite significant because that means that the cell will probably now be visible to an immune response. So it's the first step to get rid of these long-lived sleeping forms of virus with a drug that's more potent than other drugs we've used already to wake up the virus. And that's actually a big step, but it's not a cure, but it's the first step to make that cell now visible to the immune system or another intervention. Other question? Hello, Elizabeth Finkel from Cosmos Magazine. So I have two questions. The first is just a very naive one. Is it possible with what... Who reported the paper in Science that came out today? Dan. Dan, because of what you've seen in your animal studies, very early infection, and also the Mississippi baby, is it possible the fetuses are being infected in utero? So we know from studies looking at mother-to-child transmission and drugs to block mother-to-child transmission that indeed babies get infected in utero, what's considered in utero infection. That's a small proportion of infants who get infected. So we do have evidence that babies get infected in utero. And in fact, for the Mississippi child, in pediatrics the way we stratify children, whether they're infected in utero or not, is based on whether they have detectable virus nucleic acid present in the bloodstream in the first 48 hours of life. So using that definition, this child would have been considered as being infected before birth. Now, how early before birth the child is infected, we don't have a marker to tell us that. And so it is encouraging that if indeed that stratification is correct that even in a child who's infected in utero, very early treatment, and here early treatment is 30 hours of age, we still have a wide wind of opportunity there because kids can intervene as early as half an hour, hour of life in terms of this treatment strategy. So again, I want to emphasize that while we're very disappointed for this child that she requires antiretroviral treatment now to control her virus, this is really unprecedented for the field and a major step forward, that a minimal antiretroviral treatment regimen, three-drug regimen started at 30 hours of life for 18 months, can allow a child to go up treatment for 27 months. So am I right in thinking that most infants are not infected in utero? Yes, you're right. So they would be the category that might still benefit from this early intervention? So we're hoping both categories will benefit from this intervention. And one reason is that the neonatal immune system is developing and it's tolerogenic. So these memory T cells may not form as readily in a developing immune system. And my second question is, picking up a little bit of a paradox because on one hand one of the speakers mentioned, I think it was you that it was possibly just a single virus in a single cell that was enough to reactivate the infection. Given that's the case, why do we even care how much you hit down the reservoir? If you haven't hit it down to zero, it's not going to make any difference. That's actually a great question. You know, I think that the Mississippi case and other cases in the past year or so make me wonder if we will ever get rid of the entire reservoir. So we actually may end up in a situation where we get rid of a big chunk of it and have a little bit left, but we're going to need a way to control that little bit that's left. And there are a number of ways it can do that, right? Therapeutic vaccines, antibiotics and so forth. So the field has sort of in the past been split between those who just want to get rid of everything versus those who don't particularly want to get rid of everything, they just want to control it. And I actually think at the end of the day we're going to need both. The immune system really can't control the amount of virus that people have now. We know that. Most people basically do not do well. But hopefully if we can get rid of 99% of it and boost the immune system, just a little bit of immune power is all you're going to need to control what's left. And that's where the field is going. And that's going to require combination approaches, which is actually complicated to do and partly why industry is not really engaging to the degree they can. Okay, we have another question. Yes. You were the first, maybe? I don't know. I don't know. I'll go. My name is Mark DiStefano from BuzzFeed. I want to know about the relationships between vaccines and the cure and whether the attention, whether it's economic or industry has shifted away from finding a cure to developing really powerful vaccines, especially when it comes to things like the Mississippi baby, I guess, letting down a lot of people's hopes for a cure. Maybe Francois, do you feel as though a lot of the attention at the moment is on vaccines and not the cure? No, I don't think so. I think we need both anyway. We should not oppose vaccine research and cure research. And they are very much complementary. As Steve just said, we will need to combine different approaches and we probably need to strengthen the response of the host by immune-based therapy or vaccine therapy. So that's clear for me that both should be continuing parallel. And by the way, certainly as part of this is something that we will discuss this week, but as part of the IAS HIV vaccine initiative, we will strengthen the relationship between cure research and vaccine research. And Dan, maybe you can say a few words as well on that. Sure. So I'll just reiterate what Steve and Francois have said that in my view there is no tension at all between them because they are complementary. In fact, vaccine research will likely be part of interventions that are being explored for cure. So in fact, they are two sides of the same coin. They are both needed. And I don't see any tension between them. Hi, Jessi Eil from Bloomberg News. So we have heard the news about the Mississippi baby and Ole's research. I'm wondering if from that you could let us know a temperature check in terms of your optimism for a cure. Are you febrile or hypothermic, right? Are you asking me? Everyone. So I'm very optimistic for remission for pediatric patients because, again, I will say this again, it's that 27 months off antidepressant treatment with a strategy that's not the best that we can have to achieve this outcome is spectacular in my mind and really is the catalyst, I think, for us to move forward. I mean, it is a look. Of course, I have to speak about the discontinuation but nobody is speaking about the discontinuation. But you know, some of them, we have 20 patients today that stopped the treatment. It's 10 years ago for some of them that they stopped the treatment and they are still controlling their virus. So it's no reason not to continue and to be optimistic for the future. I think one other key point about the Mississippi baby, he says the 27 months off treatment with the viral under control is unprecedented. And secondly, the Mississippi baby and also the Boston patients had no immunity to HIV. So they had the extreme of very, very small amounts of virus but absolutely no immune response. The baby because the baby was treated very early, the Boston patients because they had received a transplant. So I think that's a key factor about what may have had a play in the remission and the fact that the virus came back. You know, I got a lot of people who asked me about the Mississippi case and whether it was disappointed and whether it's going to affect my enthusiasm. And obviously it's a tragic situation for the baby and the child but I'm hoping, I'm sure the child will get the best care possible and hopefully one day she will know how important she was in the history of HIV in terms of cure research. But as a scientist, these failures are actually often far more instructive than successes. And with regard to this particular case, again, it confirms what we all assumed but didn't really know that it just takes one cell that can live for years to start the whole process over. So we really now know what we need to go after. And secondly, at least for me, it has really sort of focused my research on the need for long-term surveillance that we may never be able to get rid of all the virus but we're going to have to build up the immune system in some way to control a little bit of virus. So I actually perceive the Mississippi case scientifically as a great success and I'm hopeful that the child herself will get the best care possible and will do well. Sophie? Sophie, we're here from Selection, from France. I understand yesterday in your talk, Françoise, that in the Selection satellite that the mother of the Mississippi babies may be a long-time non-progressor or kind of. May that be a part of the reason what we observed with the baby? Thank you for asking the question because it was one question that I wanted myself to ask to Debbie. Because my understanding when the case was presented is that the mother has a very low viral load and I was wondering whether the mother has a strong immune response and during the first months of birth, the baby of course may have the immunity of the mother and may have play a role in controlling the infection as well. So I'll say we've been unable to study the immune response in the mother for reasons that we can't explain at this time. But to the best of our knowledge, we've done HLA typing on the child looking for protective alleles and have not identified that. I think the main part here, and there may be unknown factors, immune factors that confer this sort of control in terms of post varemic rebound. But I will say in the period of sustained remission, the 27 months, there was no detectable HIV specific immune response. So antibody responses are cellular immune responses. So this is a case of virologic control in the absence of an immune response which is not consistent with what we know about long-term non-progressors or elite controllers. Their outcome is based on an immune response. So there was absolutely no immune response and there was no immune response because there was no virus expression in this child. So that's the best that we can answer the case at this point. So perhaps down the line we'll be able to do additional studies on maternal samples, sort of sequencing which we needed to do to confirm reemergence of infection in this child rather than reinfection from a different source. We've not been able to conduct extensive immunologic studies on the mother. Hi, my name is Tabile from South Africa. You will know the situation in my country with so many people infected and affected by HIV and AIDS. There's only just one question from the community. They just want to know when, when are the scientists finding a cure for HIV? How close or how far are we? I know it may be a bit basic but most of our people are the illiterate and the poor. They just want to know, is it possible? Is it coming any time soon? Are you able to give us a response to that? I will let the others to give their opinion but when generally people are asking me this question I say no, I will not answer. I don't know. I don't know how long it will take to get a cure or to get a treatment inducing a remission. We cannot really answer that. I personally think that we should not give any dates. We should not make what has been done for vaccines in the past to say that we will have a vaccine in... I remember in 1984 Margaret Eichler said we will have a vaccine in two years. Look, we are now 30 years after that we still do not have a vaccine. So I don't think we should give any hope today. What we know is that we should move on because there is plenty of scientific evidence, plenty of data that are telling us that we can make progress and how many years we need to get a new therapeutic strategy we don't know. Any other... You want to give your... I would say that a cure which is actually applicable to everybody around the world, many very smart people don't think it's possible or will ever be possible. And my personal opinion is that if it is possible and we can do it, it's going to take many, many years. Fred Scheich, I far out Portland, Oregon. Kind of segueing from that and you mentioned earlier about the combinations of vaccine and cure research, whatever that might be, and compounds. How do you see that rolling out? Do you feel like there's the possibility of working with two compounds, one from vaccines and other from other forms of cancer type drugs that you're working with? How do you see that rolling out? Can you do the studies with two things? Because it seems to me like that would be the magic is when you start to combine that you get the real improvement or possibilities. All I might want to answer that because that's what they're doing. I can give you a quick answer. I can say that we have such a study ongoing now and just combining this compound that I mentioned, Romadepsin, together with a therapeutic HIV vaccine that has been tested in more than 100 HIV patients already. So we have that study ongoing. We just started involving patients. So it'll be a while before we have any results, but at least it's the first combination trial. So yes. And just to follow up with maybe a triple combination or are you thinking about that? I think we're thinking about a lot of things, but we need to take one step at a time. So, and this is already a pretty big step just to combine two different compounds. Karen O'Sullivan from Channel 7 News here in Melbourne. Holly, just wondering if you can give us any more detail about your trials. Just the nuts and bolts of how long it went for. You said there were people involved, where they were from. If you can expand any further on the trial itself? Sure. So, as I said, six patients were enrolled and they were all Caucasian patients all from our own outpatient clinic at Oxford University Hospital. All were on effective antiretrial treatment. The trial was initiated in early April this year and we just, we still have just done the last follow-up. This is just literally before we came here. So, we are still in the process of analyzing the data, but the data that I'm presenting tomorrow is what we have so far. And I think that's enough at least to say that the agent was successful in doing the job that they were supposed to and that is to kick bars out of the cells. I'm afraid we have to stop. If you'd like to ask a specific question to a participant, that is possible but outside of the room because they are waiting for the room that will be used for the press conference. I just would like to thank all the participants to this press conference. I'd like also to remind you what has been told to you at the beginning, all the data are under embargo until tomorrow 2.30. Please respect the embargo. Thank you very much.