Interview with NCHIV 2015 speaker, Jintanat Ananworanich, on post-treatment viral remission
Dr Ananworanich will be joining us at NCHIV 2015 to talk about recent research into post-treatment viral remission in HIV-infected individuals.
The title of your talk at NCHIV 2015 is ‘Post-Treatment Viral Remission in HIV’. How would you define post-treatment viral remission?
We don’t know exactly how to define it, but a good working definition would be achieving viral suppression in the blood without ART for at least 12 months. We would also expect that people who are post-treatment controllers would be healthy, with no significant CD4 drop, and ideally no immune activation, unlike elite controllers. Elite controllers provide a model of post-treatment controllers because, although they are not post-treatment, they are in viral remission. However, they still have immune activation. In terms of post-treatment control, we would like to see people being healthy and without immune activation.
There have been a number of high-profile cases in the media recently, where post-treatment remission was thought to have been achieved. Of these, only the Berlin patient remains HIV-free. Clearly, the approach taken in this case is not one that can be applied to most HIV-infected patients, even those with cancer. However, are there elements of this approach that lend themselves to further investigation?
I think that, although all had transient remission, the Boston patients, who underwent bone marrow transplant, and the Mississippi baby showed that if you can sufficiently reduce the number of infected cells, post-treatment control is possible. Generally, we expect most people to have viral rebound in 2-4 weeks; these cases show that it can take much longer. With the Berlin patient, you are right, we aren’t going to try such a drastic approach, but it did show that if gene editing could be used to produce HIV-resistant cells, the reservoir could be reduced. This has subsequently generated a lot of interest in gene editing therapy and also in T-cell-based therapy, using engineered T-cells that are either HIV-resistant or carry a suicidal gene that would automatically kill the infected cell. So, I think that although very few, these cases have fuelled a lot of interest in different areas and are therefore very useful.
You yourself are a paediatrician and presumably therefore your personal interest lies in the reported cases involving newborn infants (such as the Mississippi baby, the Canadian babies and the Milan baby). What have these cases taught us about viral suppression?
The determining factor in achieving HIV remission is still unclear, but the cases involving infants do provide some clues. For example, the case of the Mississippi baby is unique in that, although the baby was treated very quickly, it clearly also had a much faster rate of viral suppression (within one month). This suggests that not only is it important to start treatment early (as recently confirmed by the START study), but also to achieve rapid viral suppression. However, in terms of the early-treated infants, this is not at all easy to achieve. Complex factors are involved in the rate of viral suppression, including genetics, viral fitness, number of cells available for infection, viral load, etc.
The START study shows that people should be treated immediately regardless of CD4, but there’s still a gap in terms of diagnosing acute infection, and, once that has been diagnosed, there’s urgency to start treatment because the acute HIV infection period is probably the first 4 weeks of infection. The problem is that children are not diagnosed fast enough. Moreover, of those children who are treated, only about half achieve viral suppression because we have very few drugs that can be used in infants. We are therefore running an NIH/NIAID-R01 funded study in Thailand, the HIV-NAT 209 study, where we’re trying to track every child born with HIV in Thailand from the moment of birth, and to start treatment as soon as possible.
The approach taken in neonates involves rapid treatment following acute infection. What are your thoughts on achieving functional cure in chronically infected individuals?
In the chronically-infected population it will be even harder to achieve remission and we might have to use multiple interventions. For example, we know that in people who are chronically infected, there is very little decay of cells carrying HIV DNA, so one approach could be to alter this rate of decay, alongside immunological-based interventions to kill existing infected cells. I think that the studies we are doing in early-treated individuals, who are probably easier to get into remission, will help us devise a plan for the chronically-infected.
We recently spoke to another NCHIV 2015 speaker, Rogier Sanders from the AMC-UvA, about his work on developing broadly-neutralising antibodies that target the gp120 envelope glycoprotein. You are also an immunologist – is this a route you are also investigating or are you looking at other immunotherapeutic tactics?
We are also going to start two studies in Thailand into two broadly-neutralising antibodies that target the CD4 binding site: VRC01 and 3BNC117. We plan to randomise people treated during acute infection to either the antibody or placebo, and then measure reservoir size. It’s unclear whether broadly neutralising antibodies can actually reduce the reservoir. It may be that they are more potent than natural antibodies and that even very little expression on the cells would allow them to bind and reduce the reservoir.
The studies will also include cART interruption to see if the antibody could achieve post-treatment control. ART interruption is an essential part of cure research, but due to misunderstandings in the field, it is perceived as being very risky, particularly that the SMART study has underlined the importance of not interrupting treatment. However, treatment interruption can be done safely within the context of cure research by carrying out very frequent viral load measurements and resuming treatment promptly with viral rebound.
What role would you envisage a vaccine playing in functional cure?
Vaccines will play a very important role. The very exciting data presented by Louis Picker on the CMV vaccine was quite remarkable because that vaccine generated an effector T-cell response and eradicated SIV infection from half the infected monkeys. This showed that if you can generate an ongoing effector T-cell response, the immune system will eventually clear these cells. These T-cell responses were also very broad and they didn’t just target the dominant epitopes, which the virus can quickly escape. Human studies are planned for the vaccine, but because this is a live viral vaccine, there remain many safety issues.
How far do you think we are from developing an approach that would achieve post-treatment viral remission in HIV-infected individuals?
I don’t know, but I think it may be achievable in certain groups of people. We already have post-treatment controllers in different cohorts and we are learning more about the predicting factors in those people and what types of immunity are associated with post-treatment control. But it will take decades to have a treatment that is broadly available to most people. Nonetheless, I am hopeful that in the next 5-10 years we could achieve post-treatment control in certain subsets of people, like early-treated adults and children.