“To cure AIDS one day, we need to eliminate cells’ viral reservoirs”
Françoise Barré-Sinoussi won the Nobel Prize for medicine in 2008 for jointly discovering the human immunodeficiency virus (HIV). She looks back at the many strategies to eliminate the cells that carry it and talks about the search for a vaccine against AIDS and her progress towards other vaccines in the future. Interview conducted by Mathias Germain
Françoise Barré-Sinoussi started research at the start of the 1970s, in Jean-Claude Chermann’s laboratory at Institut Pasteur. She was just getting to know retroviruses. These are special viruses whose genome is comprised of RNA; using an enzyme, they are able to retrotranscribe their RNA into viral DNA, which inserts itself into the genome of the infected cell. Françoise Barré-Sinoussi enthusiastically devoted herself to the relationship between retroviruses and cancer in mice, until she was contacted by Jean-Claude Chermann and Luc Montagnier to conduct virological research into the hypertrophic lymph nodes of a patient in the early stages of AIDS. In January 1983, the utmost needed to be done to cope with the epidemic. She worked methodically and discovered the human immunodeficiency virus (HIV). The race was on to decode its mechanisms and develop treatments. Today, after significant progress and a Nobel Prize, the combat continues with the ultimate hope of rendering HIV harmless.
La Recherche Remarkable progress has been made in the treatment of patients with HIV and in prevention. Is this the beginning of the end of AIDS?
Françoise Barré-Sinoussi Progress has undeniably been made. Today we have a wide range of antiretroviral treatments that have reduced the mortality and morbidity of people infected with HIV. These treatments have brought AIDS from a deadly disease to a chronic disease. In Europe and North America, the life expectancy of seropositive patients has increased by ten years since 1996, the date when antiretroviral drugs were introduced. For someone who started their treatment in 2008, sufficiently early after infection, the life expectancy is now 73 years old for men and 76 for women, about as high as for the general population. However, can we speak of “the beginning of the end of AIDS”? I don’t think so; the treatments are not a cure. A lot of effort remains to be made to get to this. And of course, vigilance is still required in terms of prevention.
You are greatly involved in international research networks in Asia and Africa. Is the population there benefitting from treatments?
Yes, African and Asian countries have benefited from this progress in treatment. It was estimated in 2016 that about 19.5 million infected people around the world had access to antiretroviral drugs. But the glass is only half full! There remains as many people who need to receive treatment. In some regions, the issue of access to medication is even more evident; 75% of people living with HIV in Western and Central Africa still do not have access to antiretroviral drugs. This is all the more cruel as studies have clearly shown that for infected patients, starting antiretroviral treatment early on is beneficial. Severe morbidity is reduced by half in patients who start antiretroviral treatment very early, compared to those who take it later, whatever the severity of the infection. In fact, since these results, it is recommended to treat everyone infected as soon as a diagnosis has been made. These recommendations were drawn up in 2015 by the World Health Organisation.
Can you remind us what the reference treatment is?
The therapy consists of combining three antiretroviral drugs (ART). They do not cure the infection, but prevent the virus from multiplying in the body and allow the immune system to become stronger. Such treatment renders the virus undetectable, and is accompanied by a rise in CD4 T lymphocytes (the cells that are the preferred target of the virus), reducing the risk of severe morbidity. The treatment also reduces the risk of passing on the virus to someone else. However, it does not eliminate the viral reservoirs, comprised of various sub-populations of cells containing the latent virus and which are formed in the first days after infection. Treatment therefore needs to be continued for life to keep the infection at bay.
Can this treatment be simplified?
Several strategies are being studied. One avenue consists of reducing the treatment so that the patient has only one or two antiretroviral drugs to take per day. We are also looking into the possibility of concentrating the treatment over several days or delivering prolonged-release drugs, whose active ingredient is released slowly into the blood over several weeks. New families of antiretroviral drugs are also being studied, such as attachment or maturation inhibitors.
How can the virus be prevented from fixing?
We are trying to act on the viral protein that HIV uses to attach to the host cell. New strategies are underway, particularly since 2013, by characterising broadly neutralising antibodies that attach to this viral protein and prevent it from attaching to the cell receptor (CD4). Another strategy consists of using gene therapy to modify the cell co-receptor (CCR5) to prevent virus attachment.
How do the maturation inhibitors work?
They intervene at a particularly late stage in the viral replication cycle, after the virus has left the cell. They prevent the viral proteins from becoming fully operational. By doing so, they stop the progression of the infection. But these molecules are still in the clinical development phase.
All these advances control the infection. But what progress could be made to cure HIV one day?
Viral reservoirs would have to be eliminated entirely. When the virus infects a cell, its genome is inserted into the genome of the cell, where it can remain in a latent state without producing viral proteins. The reservoir cells remain invisible to the immune system, and can proliferate even when the patient is undergoing treatment. When the cell divides, it also multiplies the genome of the virus, which may be reactivated if treatment is stopped.
Are these reservoir cells always T CD4 lymphocytes?
No, these are not the only cells that act as a reservoir for the virus. It can hide in other immune cells such as macrophages (*). In fact, these reservoir cells are not just found in the blood, but also in numerous other parts of the body: bone marrow, brain, intestines. Over the last few years, we have learned that a sub-population of T-cells in the lymph nodes (known as T-helper cells), play a significant role as reservoirs.
These reservoir cells are a threat to patients, but some manageto control them afterstopping treatment. How so?
You are talking about patients in the Visconti cohort; twenty or so people who have stopped their treatment but in whom the viral load (the number of viral particles present in the blood) remains undetectable. We don’t yet have all the elements to understand exactly what happened. For the moment, it has been shown that these patients have very few viral reservoirs. They were treated very early on after exposure to the virus; the treatment probably limited its spread.
Once the treatment was stopped however, the virus could have replicated...
Indeed, meaning that something else enabled these people to control these latent reservoirs. We know that, unlike what happens in so-called “elite controllers” who spontaneously control the infection without treatment, it is not the CD8 lymphocytes which eliminate the latent reservoirs. Recent work has shown that innate immune response cells are involved in the control operated by the Visconti patients, particularly NK (natural killer) lymphocytes. These cells are one of the body’s first line of defence, able to destroy abnormal or infected cells without prior activation. Studies have shown that the NK lymphocytes in the Visconti patients are special. On their surface membrane, they express a variety of receptors that differ from those of non-controller patients.
Is the innate immune response key in controlling the infection?
Yes. Work on animal models and also on those rare patients who control the infection spontaneously or after treatment, tend to show the important role of the innate response in the subsequent control of the infection. Now, we are trying to understand if this innate response induces a specific, adaptive immune response. But I insist, the innate response and the inflammatory response clearly play a significant role. We know that when the inflammatory response is too high, the latent reservoirs are maintained in the system. But if the inflammatory response is not excessive, the immune cells are beneficial against the viral reservoirs. It is a question of balance. It is complex, but we are starting to understand. These observations on reservoir cells also bring us closer to issues facing oncologists: there are links between the behaviour of reservoir cells and tumour cells.
Explain this link with oncology...
We discovered that the reservoir cells express molecules on their surface common with cancer cells, such as PD1 or CTLA4 molecules. Once activated, these molecules inhibit the function of the T-cells, which become powerless against these cells. Anti-PD1 and anti-CTLA4 antibodies have been developed in oncology. They remove these obstacles and strengthen anti-tumour immunity. These antibodies have achieved remarkable results in some patients suffering from melanoma or lung cancer.
Can they be used to eliminate reservoir cells?
Several studies have started in France and the United States. But this is difficult to implement; we cannot suggest that a patient with HIV, living normally thanks to antiretroviral treatment, tests an anti-cancer drug. The people included in these studies are HIV patients who have developed cancer. They are treated for their cancer with these new molecules. For those who accept, analyses are conducted in parallel to observe the effects on the latent reservoirs and on the anti-HIV immune response.
Are we able to identify the reservoir cells properly?
This is a major priority for current research. If we want patients to go into lasting remission, we must have better markers to identify and quantify these latent reservoirs. Several examples have shown this. First there were the “Boston patients”, two HIV-positive men who had had a bone marrow transplant to treat leukaemia. After this treatment, all traces of the virus had disappeared from their blood! They then stopped their treatment. Several months later, the viral infection took hold again and they had to continue their antiretroviral drugs. These patients reveal the insufficiencies in our detection of latent reservoirs.
Is progress being made in this field?
Yes. The team of Monsef Benkirane from the Human Genetics Institute in Montpellier, discovered a new marker, the CD32a receptor. His work showed that the cells that express this receptor were rich in latent virus. This is an important step. But other markers are needed to improve the detection of latent reservoirs, to quantify them and possibly target them therapeutically.
Is it possible to wake the virus up from latency to repair the viral cell and eliminate it?
This is the shock and kill strategy. Much work has been done on this; in vitro, several teams have shown that the virus can be forced out of latency using molecules that unravel the DNA to expose the viral sequence to transcription factors. This sequence produces viral DNA. Then, immunotherapy or vaccines are used to stimulate the T CD8 lymphocytes and eliminate the reservoir cells where the virus was reactivated. Unfortunately, initial tests in patients were not markedly successful.
Should this strategy be abandoned?
No, this is only the beginning. Are we using the right dose of agent modifying the chromatin (**) ? Do we have the right molecules? We have to continue. This work has revealed the mechanisms involved in viral latency, epigenetic phenomena and the role of transcription factors. But we are a long way from understanding everything. We need to be able to rapidly eliminate the cell where the virus awakes.
Can the new tools developed to edit the genome be used to eliminate the viral DNA?
In vitro, teams used CRISPR-Cas9 molecular scissors to cut the viral sequence from the cell’s DNA. But research has also shown that this type of manipulation leads to mutations that enable the virus to resist. Once again, we are learning as we go. Furthermore, there are strategies to genetically modify the immune cells, so that they are effective against the reservoir cells. This strategy is inspired by CAR-T cells, developed against some cancers.
And where is research into a vaccine against HIV?
This is also one of the major priorities of research. There was a glimmer of hope in 2009 with a trial in Thailand, which showed that the candidate vaccine (a combination of two vaccines) reduced the risks of infection by 31% in those vaccinated. Very modest efficacy. A new trial currently underway in South Africa is repeating this strategy, but with a slightly different vaccine.
Has the discovery of broadly neutralising antibodies brought progress in this field?
This is indeed an important discovery. They have been found in a small number of patients. These neutralising antibodies are able to control different strains of HIV. Their structural nature has enabled very powerful neutralising antibodies to be produced. They were injected into monkeys and humans, and showed encouraging levels of protection. But we need to discover which vaccine can induce antibodies that are as effective... The search for a vaccine against HIV has revealed how poor our theoretical knowledge really is in vaccinology. Today, we still do not know how a vaccine as effective as the one against yellow fever actually works. For this reason, we need answers to these fundamental questions.
Research into HIV has advanced the vaccines of the future. What other fields have benefitted?
The first example that comes to mind is hepatitis C. An effective treatment has been developed and today we can cure it. This is work that has arisen out of research into HIV. Other fields have also benefitted from this research. In cell biology, we can identify molecules that are used as receptors; in immunology, we know more about the function of T-cells... I regret that we do not speak enough about this progress. We are wrong, as some believe we have given too much money to the fight against AIDS. This is in fact bringing positive and negative lessons concerning public health issues that the whole world will have to face in the coming years. We have stopped thinking in terms of one pathology; HIV research is useful for global health.
(*) A macrophage is an innate immune system cell able to absorb cell debris and pathogenic agents.
(*) Chromatin corresponds to more or less compacted DNA, wound up by molecules.
“ROBIN CAMPILLO’S FILM IS A REMINDER THAT WE SHOULD NOT LET OUR GUARD DOWN”
Robin Campillo’s film, 120 Beats Per Minute, released this summer, is important. It recalls vividly the urgency and dramas at the start of the epidemic. We could fall back into this situation much more quickly than we believe possible. I’m very afraid of that! This ?? must be seen by politicians and young people. Young people so they understand that they need to protect themselves. Treatment does exist, but it’s for life! It’s not easy to take it every day. In addition, being in contact with the virus increases the possibility of developing cardiovascular diseases, central nervous system disorders, etc. We mustn’t let our guard down! There are negative signs pointing to the fact that, in some populations, the number of people getting infected is on the rise. Fortunately, there is now preventive treatment that can be taken prior to risky sexual contact (PrEP). The former minister for health, Marisol Touraine was very brave to take the decision to offer PrEP in France and ensure it is reimbursed. However, we need to continue to have politicians who take brave decisions, otherwise we could return to a catastrophe”, states Françoise Barré-Sinoussi.
> INTERVIEWEE
Françoise Barré-Sinoussi
Virologist
1947 ▪ Born in Paris.
1971 ▪ Following studies in biology and biochemistry, she joined Jean-Claude Chermann’s laboratory at Institut Pasteur.
1974 ▪ She got her doctorate in virology.
1976 ▪ She was hired by Inserm and worked at Institut Pasteur.
1983 ▪ She discovered HIV from biopsies on a patient’s lymph nodes. Author of the first article on HIV in Science.
1988 ▪ She became head of the retroviral biology laboratory. She started research programmes into the characteristics of the virus and the disease’s developer host.
2008 ▪ She won the Nobel Prize for Medicine.
SINCE 2010 ▪ Involved in many organisations, she is the honorary president of the International Network of Instituts Pasteur. From 2012 to 2014, she was President of the International AIDS Society.
