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By Hanna Kurlanda-Witek

Françoise Barré-Sinoussi received the Nobel prize in Physiology or Medicine in 2008 together with Luc Montagnier, “for their discovery of human immunodeficiency virus”; and Harald zur Hausen “for his discovery of human papilloma viruses”.

In an interview for IAVIReport (the Publication on AIDS Vaccine Research), Françoise Barré-Sinoussi spoke about what it was like to be one of the discoverers of the human immunodeficiency virus (HIV). “As a scientist it was really wonderful because we were making a hypothesis and defining approaches to try to confirm this hypothesis (...). But as a human being, it was really awful.” Barré-Sinoussi was one of a handful of scientists working to identify the virus causing this strange new disease, which many believed at the time, only affected homosexuals, heroin addicts, Haitians and haemophiliacs. By the end of 1983, nearly 1300 people had died of AIDS (acquired immune deficiency syndrome), the disease caused by HIV, in the United States. Since the beginning of the epidemic, an estimated 70 million people have been infected with HIV worldwide, and 35 million have died of AIDS.
Francoise Barré-Sinoussi was born on July 30, 1947 in the 19th arrondissement of Paris. She was drawn to science at an early age, which, she recalls, could be reflected in her grades at school when compared to other subjects. After completing her baccalauréat in 1966, Barré-Sinoussi considered becoming a doctor, but eventually chose to study at the Faculty of Sciences at the University of Paris, thinking it would be a cheaper option that wouldn’t burden her parents financially. During university, Barré-Sinoussi wanted to volunteer at a lab to gain some firsthand experience, but found it difficult in finding a free position. A friend helped her find a place at the Pasteur Institute, which at that time was located at Marne-la-Coquette, close to Versailles. Barré-Sinoussi joined Jean-Claude Chermann’s laboratory, where she was first introduced to retrovirology and quickly became absorbed with studying the links between retroviruses and cancer in mice. Lab work became the centre of Barré-Sinoussi’s studies, and she attended university only to pass exams. Chermann became Barré-Sinoussi’s PhD advisor and would remain her mentor at the Institute for many years to come.
Barré-Sinoussi’s PhD project focused on the use of HPA23, a synthetic molecule, to suppress reverse transcriptase, the enzyme responsible for DNA conversion from a retrovirus’s RNA genome. The study was conducted on the Friend virus, a retrovirus which causes leukaemia in mice. Barré-Sinoussi was successful in impeding the spread of the disease in culture, and was awarded her PhD in 1974. Afterwards, she completed a one-year post-doc with Robert Bassin, at the National Cancer Institute of the National Institutes of Health in Bethesda, Maryland. Barré-Sinoussi remained in the field of retroviruses and cancer, working to determine the viral target of the Fv1 gene product, which was associated with the replication of the leukaemia virus. She returned to France to marry, in 1978, and again joined Chermann’s laboratory, in the unit of Professor Luc Montagnier, after having been awarded an INSERM (National Institute for Health and Medical Research) position.

In December 1982, Willy Rozenbaum, a doctor working at the Claude-Bernard Hospital in Paris, and Françoise Brun-Vézinet, a virologist, approached Chermann’s group to discuss the possibility of forming a project with the aim of identifying a newly-emerged virus. Rozenbaum was the first clinician to encounter the disease in France, after reading about a perplexing occurrence of Pneumocystis pneumonia in five young homosexuals in Los Angeles. Rozenbaum had read the report one morning in the Morbidity and Mortality Weekly Report, issued by the Centers for Disease Control and Prevention (CDC), and was visited by two patients with the same symptoms later that day. The number of cases was soon to grow. In 1982, the illness became known as AIDS. Rozenbaum believed that the infectious agent responsible for this marked weakening of the immune system could be a retrovirus, and Montagnier and Barré-Sinoussi set out to find whether a retrovirus could indeed be the culprit. At that point, there was only one known human retrovirus – Human T-lymphotropic Virus (HTLV-1), which transformed T cells, lymphocytes that are pivotal in the functioning of the immune system by directing a targeted immune response to the pathogen. Montagnier and Barré-Sinoussi considered that this could be a different virus. The problem was that the virus infected T cells attached to CD4 proteins, causing their depletion, and so it was very difficult to isolate the virus from these cells. The group decided to test a lymph node biopsy from an AIDS patient. The liquid from the cell culture was tested every three to four days to check whether there was any reverse transcriptase (RT) activity. Some RT activity was observed in the second week of the experiment, but this decreased linearly with T cell death. The group became concerned that they would soon lose the virus, maybe as a result of toxicity of the T cell components, but the addition of fresh blood from a donor again boosted T cell death and RT activity. This meant that the virus in culture was infecting the T cells. Experiments were also conducted to determine the virus’s cross-reactivity with HTLV-1 proteins, but little or no cross-reactivity was established. In just several weeks, the team of Montagnier and Barré-Sinoussi had discovered a new human virus. Microscopic images of the virus were taken in February by Charles Dauguet at the Institute, and the first report on the virus, named Lymphadenopathy Associated Virus (LAV), was published in Science in May 1983. In the same year, US health officials reported that female partners of men with AIDS were also afflicted with immunodeficiency. It was found that children could also bear the disease, and it was soon established that the disease could be passed from mother to child; it became evident that this was only the beginning of an epidemic. By the end of 1983, the CDC had excluded casual contact, as well as food, air, water and surfaces as a mode of transmission. There was still no diagnostic test available for virus detection in blood. The group at the Pasteur Institute decided to focus solely on LAV, and put together a team of clinicians, immunologists and molecular biologists that would determine that LAV was the agent responsible for AIDS. A serological test was soon developed, which led to a diagnostic tool for blood testing, a much-needed means to prevent transmission of the disease by blood. In 1984, Robert C. Gallo and, independently, Jay. A. Levy published articles demonstrating that they had isolated the retrovirus causing AIDS – named HTLV-IIIB and ARV (AIDS-associated retrovirus) by Gallo’s and Levy’s groups, respectively. In 1986, the International Committee on Taxonomy of Viruses decided to name the virus HIV (Human Immunodeficiency Virus).
The virus now had a name, but another decade would pass before effective combination treatment became widely available. Scientists, among them Barré-Sinoussi, had no idea how massive the epidemic was going to be, but “worked like crazy”, as Barré-Sinoussi herself phrased, to learn about how the infection spread through the body, and attacking which process could inhibit the retrovirus’s activity. The virus fuses with the membrane of the cell, specifically the CD4 receptor of T cells, after which RT in the virus begins to rewrite the virus’s RNA into DNA. The host cell incorporates the DNA into its own genetic material. It was quickly understood that treatment should first and foremost deactivate RT. Through careful monitoring of CD4 cells in patients, it was found that CD4 cells are correlated with the HIV RNA concentration, known as the viral load; the peak of the viral load leads to a drop in CD4 cell numbers. It is now known that HIV establishes permanent reservoirs in the host even three days after infection. Another characteristic of infection is microbial translocation in the intestinal tract – the body’s reaction to a drastic reduction of T memory cells with CCR5+ CD4+ receptors. In 1987, doctors were provided with the first antiretroviral drug that they could prescribe to AIDS patients, azidothymine (AZT), a drug with many side effects, but which could at least temporarily halt the spread of the virus in the body, at a time when no other option was available. The first protease inhibitor was approved in 1996, marking the beginning of highly active antiretroviral therapy, or HAART. The use of several drugs (combined therapy), can suppress the replication of the virus, and a drop of 60-80% in AIDS-related deaths was reported in the following years. AIDS is still incurable, but has become a treatable disease. It was a moment when scientists and doctors could pause for breath – patients finally had a solution. But as Barré-Sinoussi admitted in an interview in 2014, “I rapidly developed depression”. The years spent working to find any form of therapy amid the accelerated spread of HIV was overwhelming to many professionals working in the AIDS-related field.

The current form of treatment is not ideal; with termination of the treatment, the virus starts to replicate again and viral reservoirs start to spread within 2-8 weeks. As Françoise Barré-Sinoussi stressed during her lecture at Lindau in 2015, lifelong treatment is not sustainable long-term, and novel treatment is needed for comorbidities on antiretroviral therapy, such as cancer and cardiovascular diseases, as well as drug resistance. In terms of a cure, or vaccine for HIV, Barré-Sinoussi supposes there will not be a standardised, one-size-fits-all approach. After nearly 40 years of research, HIV is still not fully understood – it has a high level of genetic variability and is also specific to the host. The speed of the replication of the virus is also dependent on how early the host begins treatment; an example of long-term post-treatment remission is the so-called Visconti cohort, a French study of a group of 20 HIV positive patients, who were treated soon after infection and were able to naturally control the spread of the virus, without any form of treatment, for a median of 10 years. These optimistic cases are known to scientists as HIV controllers, or elite controllers, possessing a high level of natural killer cell activity, cells whose role in the organism is to destroy pathological agents, such as tumour cells and virally infected cells. But while research must remain ongoing, it is equally important to manage the spread of infection, particularly in resource-limited countries, which are home to the majority of the 30-50% of people who do not know they are infected. Barré-Sinoussi recognised the great importance of working in developing countries. She first visited Africa in 1985, as part of a World Health Organisation workshop in the Central African Republic. Since then, Barré-Sinoussi has been a strong advocate for international cooperation in the AIDS epidemic, including the exchange of scientists. One such positive example of cooperation and education resulting in a significant impact, is Cambodia, a very poor country, where over 90% of HIV positive patients are on antiretroviral treatment. It was in Cambodia that Barré-Sinoussi learned that she, as well as Luc Montagnier and Harald zur Hausen were recipients of the 2008 Nobel Prize in Physiology or Medicine. Since 1992, Barré-Sinoussi was the head of the Biology of Retroviruses Unit at the Pasteur Institute. Between 2012 and 2014, she served as President of the International AIDS Society.
Françoise Barré-Sinoussi believes that HIV/AIDS has changed the face of research. Never before had patients appealed so vociferously to both politicians and scientists to find a means of treating an illness. Normally hidden from the world in laboratories, scientists became continuously approached by patients, who not only wished to learn about the disease, but also wanted to participate in the global battle on how to fight the epidemic and win. Since 2005, there has been a 20% drop in mortality from AIDS, the first such decrease since the beginning of the epidemic. What is crucial at this point is to educate others on prevention, and strive for access to treatment. From the perspective of research, as Barré-Sinoussi said in Lindau in 2015, HIV was discovered thanks to basic research, after which tools were developed for prevention. Now basic science is needed again.
The other face of AIDS, that makes the disease distinct from other widespread diseases, is the stigmatization of AIDS patients. As the writer Susan Sontag wrote, AIDS is “not just a biological disease but something much larger—a social and political category replete with its own punitive metaphors”. This is an issue that Barré-Sinoussi raises in every interview. The discrimination of those with HIV will defer their treatment and inevitably lead to an increase in new HIV infections.
Françoise Barré-Sinoussi has dedicated her life to AIDS research, and is convinced a cure for the virus she co-discovered 35 years ago, will one day be available. But AIDS will not disappear. Millions still die each year from vaccine-preventable diseases. As Barré-Sinoussi explained in Lindau, only an integrated and coordinated strategy against AIDS is the answer to restricting the epidemic.
Bartlett, J.G. (2006) Ten years of HAART: Foundation for the future. Medscape
Hu, W.-S. and Hughes, S.H. (2012) HIV-1 Reverse Transcription, Cold Spring Harbor Perspectives in Medicine, Oct 2(10).