Having proven effective in reducing the number of new HIV infections in men, circumcision also appears to play a role in the reduction of HIV incidence in women. These findings are from the study ANRS 12126 coordinated by Professor Bertran Auvert (Inserm U1018, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré) and conducted in the township of Orange Farm in South Africa. They will be presented as an oral communication by Kévin Jean (Inserm U1018) at the 20th International AIDS Conference organized by the International AIDS Society and held at Melbourne from 20 to 25 July 2014

The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have, since 2007, recommended considering circumcision as a complementary strategy in the prevention of HIV infection in men. These recommendations are based on the study ANRS 12165, begun in 2002 in Orange Farm in South Africa by Professor Bertran Auvert (Inserm U1018, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré), the results of which have been confirmed by two other trials conducted in Kenya and in Uganda. This strategy has been deployed principally in regions of South and East Africa where the rate of HIV infection by heterosexual transmission is high and the rate of circumcision is low.

In the framework of a previous study (ANRS 12126), Professor Bertran Auvert’s team has shown that circumcision seems to be well accepted by the male population when it is offered in real-life conditions. In Orange Farm, many men are willing to undergo circumcision (the rate of circumcision has increased from 12% to 53%) and the number of new infections in circumcised men has decreased (half as many new infections as in uncircumcised men). But what about women?

Kévin Jean and Bertran Auvert, together with their colleagues at the NICD/NHLS in Johannesburg, present, for the first time, on the occasion of the 20th International AIDS Conference of the International AIDS Society, the first data on the indirect effect of male circumcision on women.

In women who have intercourse only with circumcised men, circumcision appears to reduce the prevalence (proportion of people infected) and the incidence (rate of new infections) of HIV infection, and does not seem to promote risky behavior (increase in number of sexual partners, non-use of condoms).

The data are from the combination of three cross-sectional studies conducted in 2007, 2010 and 2012 among 2452 women aged 15 to 29. Blood test results, data on sexual behavior, and circumcision status of male sexual partners were recorded. First, the scientists compared the rate of HIV prevalence in women who only had circumcised sexual partners with the rate of HIV prevalence in women who had uncircumcised sexual partners. Over 30% of women reported having had sexual relations only with circumcised men. The rate of HIV prevalence in these women was 17.8%, whereas it was almost twice as high (30.4%) in women who had sexual relations with uncircumcised men.

Second, they used a mathematical model to estimate the HIV incidence rate in these two groups of women for the same period. The rate of new infections in women who only had circumcised sexual partners was 20% lower than in the other women.

These results confirm the importance of voluntary circumcision programs in national HIV/AIDS prevention programs.

The risk of transmission of HIV and of hepatitis C virus in intravenous drug users can be reduced significantly by means of support and educational sessions delivered by their peers.
This type of community intervention, which is easily transposable, has been evaluated in the framework of ANRS AERLI, a study conducted jointly by the nonprofit organizations AIDES, Médecins du Monde and by Inserm U912 (Marseille). The results were presented in an oral communication at the 20th International AIDS Conference organized by the International Aids Society and held in Melbourne (Australia) from 20 to 25 July 2014.

In all, 288 sessions were conducted among 113 drug users recruited in 8 centers specialized in offering help in risk reduction for drug users (CAARUD). A control group of 127 drug users, comparable in terms of drug injection history, age and sex, was set up in 9 other centers. All participants were questioned, at inclusion and again 6 and 12 months later, on injection behaviors involving a risk of transmission of hepatitis C virus and of complications at the injection site.

Data analysis revealed a significant benefit of the educational intervention. In the “Intervention” group, there was:

– a 43% decrease in injection practices involving a risk of transmission of hepatitis C virus (44% of drug users reported at least one unsafe practice before the intervention versus 25% 6 months later);

– a 41% decrease in complications at the injection site (66% of drug users reported complications before the intervention versus 39% 12 months later).

“In comparison with the control group, we observed a major effect of peer-to-peer education on practices that run the risk of infection transmission,” commented Patrizia Carrieri (Inserm U912). “This is all the more valuable as a large proportion of these drug users remain on the margins of the health care system.”

This type of intervention has two other advantages: it is inexpensive and is easily implemented in centers for drug users.

“This trial also demonstrates the relevance of community health care interventions, including in research, because the intervention model tested here derives directly from the peer support practices used by nonprofit organizations like AIDES and Médecins du Monde” emphasize Jean-Marie Le Gall, AIDES and Marie Debrus, Médecins du Monde.

“Given the observed benefits, said Professor Jean-François Delfraissy, ANRS (France REcherche Nord&sud Sida-hiv Hépatites) Director, it is now conceivable to set up the community intervention on a larger scale, thus enhancing risk reduction among drug users.

The first results of the pilot phase of the trial ANRS 12249 TasP show that the repeated offer of screening for HIV has been well accepted by a rural population in South Africa. The challenge remains of bringing infected individuals into health care facilities for treatment of the infection. These results were presented as an oral communication at the 20th International AIDS Conference organized by the International AIDS Society and held at Melbourne (Australia) from 20 to 25 July 2014.

Launched in March 2012, the ANRS 12249 TasP (Treatment as Prevention) Trial is one of four international randomized trials designed to assess the efficacy of the TasP strategy in a large population. It is conducted the province of KwaZulu-Natal, South Africa, one of the highest prevalence areas in the world, and the highest in South Africa (16.9% in 2012 according to the latest national survey of the general population).

In this trial, 22 geographical zones (“clusters”), each of approximately 1000 inhabitants, were defined and randomly divided into two groups (an intervention group and a control group comprising 11 clusters). All inhabitants were routinely offering repeated (every six months) rapid HIV testing in their homes. In the intervention group, people found to be seropositive were offered immediate antiretroviral treatment, whatever their CD4 cell count. In the comparison group, treatment was offered according to currently recommended South African Department of Health guidelines. Mobile clinics worked in each cluster to expedite access to care.

Results from the pilot phase of the trial, were presented at the international HIV meeting in Melbourne. This pilot phase was conducted in 10 geographic clusters containing over 12,000 residents above 16 years of age, and followed up for between 12 and 18 months. HIV status was determined in close to 9,000 of these individuals, either because they reported that they were seropositive or because they agreed to rapid HIV testing.

The initial findings are as follows:

HIV status was determined for 82% of those contacted, meaning that home-based testing was acceptable to this population. Among people who were found to be seronegative at the first home-based contact, 85% agreed to a second HIV test at the next home visit.

– Scientists also found a prevalence of HIV infection of 31%, much higher than the initial estimate.

– Around 25% of the 2,570 HIV infected individuals learned of their HIV status through the study.

– In respect to those diagnosed with HIV infected individuals and not already receiving therapy only 48% presented to a clinic within six months.  63% were linked within a year.

– In the intervention group, 80% of those with CD4 >350 cells/mm3 received therapy.

“These initial results are very important,” pointed out Professor François Dabis (Institut de Santé Publique, Epidémiologie et Développement, Inserm U 897, Bordeaux), one of the co-investigators of the trial, “because they validate the feasibility of the TasP strategy, which aims to test and treat the whole adult population so as to curb transmission.

“Validation of phase I of this trial is essential,” explained Professor Jean-François Delfraissy, Director of ANRS (France REcherche Nord&sud Sida-hiv Hépatites). “We can therefore pursue the trial.” The study entered its second phase in June 2014. The first results on the effect of TasP on the incidence of HIV infection in the population should be known by the end of 2016.

Many medical situations require a supply of red blood cells—anaemia, road accidents and chemotherapy, for example. But there is a genuine shortage of blood. Researchers throughout the world are therefore working hard to find solutions to alleviate these shortages, and their sights are set on the potential for creating an unlimited supply of red blood cells, platelets, etc., from stem cells as required. Naomi Taylor, an Inserm Research Director, and her team at the Molecular Genetics Institute of Montpellier (CNRS/Montpellier University) have just taken an important step in this direction. They show that two substances—glucose and glutamine—dictate the route taken by a blood stem cell in becoming a red blood cell or some other type of blood cell.
This research is published in the journal Cell Stem Cell.

The lifespan of a blood cell can vary greatly—from several decades for some lymphocytes to 120 days for a red blood cell, 8 days for platelets, or just 1 day for neutrophils. The body therefore has to replace some of these specific cell types on a daily basis to ensure that the requirement for “new” blood is met, while maintaining the equilibrium between the different types of blood cells.

Many research studies carried out in the last few decades have focused on elucidating the role of certain cytokines in promoting the multiplication of blood stem cells and their differentiation into red blood cells, white blood cells, or platelet precursor cells Thus EPO has become well known for stimulating and promoting the multiplication of red blood cells, whereas GM-CSF, for example, stimulates the multiplication of monocyte/macrophage type cells, the famous circulating “scavenger” cells Cytokines such as EPO and GM-CSF are used to help with haematopoietic reconstitution after surgery, during cancer chemotherapy, following a bone marrow transplant or during infection with the AIDS virus (HIV) for example.

However, it seems that these cytokines, although they play a decisive role, are not enough to ensure commitment to the various blood cell lineages. The question thus arises regarding the additional parameters and factors that direct the haematopoietic stem cells more effectively toward one cell type rather than another.

In the course of differentiation, many cell divisions take place during which the daughter cells acquire their unique characteristics. This process does not require energy alone; it also requires molecules such as amino acids, nucleotides and lipids to synthesise proteins, DNA and RNA, and membranes, respectively, for the new cells.
In the present study, Leal Oburoglu, a final year PhD student, showed that glutamine, the most abundant amino acid in the blood, is indispensable for a blood stem cell to become a red blood cell, particularly because it enables the production of nucleotides. Tests conducted in vitro in the laboratory and then in vivo in mice showed that blocking the use of glutamine or its transporter prevents blood stem cells from becoming red blood cells. Under these conditions, the blood stem cells will then differentiate into monocyte/macrophage type cells.

Conversely, if glucose breakdown to provide energy in the form of ATP (glycolysis) is prevented, nucleotide synthesis is then enabled. This has the overall effect of increasing the production of red blood cells from haematopoietic stem cells (erythropoiesis).

In other terms, the coordinated and targeted use of glutamine and glucose for nucleotide synthesis may enable the stem cell to provide more red blood cells.
For the first time, a study has brought to light that metabolic resources outside the cell control the destiny of the blood stem cell.
For Naomi Taylor and Sandrina Kinet, who coordinated this study: “It is fascinating to think that one day we may be able to bring about differentiation of blood stem cells ‘on demand’ by influencing the metabolic state of the cell.”

When the body receives an injury to the skin, a signal is sent to the brain, which generates a sensation of pain. Teams led by Priscille Brodin in Lille[1] and Laurent Marsollier in Angers[2] have studied lesions in patients with Buruli ulcer, a tropical disease. In an article published in the journal Cell, they show that, despite the extent and severity of these wounds, they are less painful than others that seem relatively minor (e.g. scratches, low-degree burns). They discovered an analgesic mechanism that limits the transmission of pain signals to the brain. An understanding of this mechanism may be useful in developing new drugs for pain relief.

Buruli ulcer (caused by infection with Mycobacterium ulcerans) is the third most prevalent mycobacterial disease, after tuberculosis and leprosy. This tropical disease, which mainly affects children, causes ulcerative cutaneous lesions. The destruction of skin tissue is caused by mycolactone, a toxin secreted by the bacterium. Despite their size, the lesions are not especially painful in the early stages of the disease, explaining why patients are slow to seek medical help. The researchers explored the mechanism that causes these lesions to be painless.

© Inserm / Conception Clerc-com – Simar Thibault

Until then, it had been thought that the lack of pain in the early stages of the disease was related to the destruction of nervous tissue. In the present study, the researchers show using infected mice that this hypothesis is not supported by nerve degeneration, which occurs only in the advanced stages of the disease. They also injected the toxin into mice to observe its effects on the animals’ sensitivity. The researchers show that the presence of the toxin can inhibit pain on its own, with no effect on the nerves.

“The bacterium, or more specifically its toxin, mycolactone, can interact with neurons and prevent the transmission of nerve signals, explaining the painless nature of the lesions,” explains Laurent Marsollier, a research fellow at Inserm.

A state-of-the-art imaging technique was used to demonstrate that mycolactone interacts with a neuronal receptor (angiotensin receptor 2), causing leakage of potassium. The potassium efflux causes neuronal hyperpolarisation, limiting the transmission of nerve impulses—which carry the pain signal—at local level.

The researchers then blocked the expression of this neuronal receptor in mice infected with the bacterium. Blocking the receptor prevented it from interacting with the mycolactone toxin, which re-established the animals’ sensitivity to pain, thus providing in vivo confirmation of the mechanism identified.

The Mycobacterium ulcerans bacterium employs a novel infection strategy by using the toxin it secretes to prevent the pain associated with the lesions it causes.

“The discovery of this mechanism, which limits pain in the cutaneous lesions during the early stages of the disease, opens up new possibilities in the search for new drugs to prevent pain,” says Priscille Brodin, Inserm Research Director and co-author of this study.

Indeed, the molecule that can block the action of the receptor does not belong to the class of analgesics in current use, such as paracetamol or opiates such as morphine. Generally speaking, clinicians are hoping for new drugs to fight pain, since the existing drugs all have limitations of greater or lesser importance in the context of personalised medicine.

Finally, according to the researchers, the receptor identified may be a target of choice, since another study[3] showed that blocking it led to the reduction of pain in patients with herpes infections.

© OMS / Dr A. Chauty, AFRF, Benin

How long does the immune memory response produced by vaccination last? Is it similar to that induced by the infection itself? New information on the A(H1N1) pandemic influenza virus has just been brought to light by researchers at Joint Research Unit 1135, Cimi-Paris (Centre for Immunology and Infectious Diseases – Inserm – Pierre and Marie Curie University). They have shown that the immune response induced by vaccination is still strong one year later, and that it is similar to that produced by a moderate infection. Their findings have been published in the Journal of Clinical Investigation.

Influenza A virus subtype H1N1, originating in pigs, birds and humans, swept across the world between June 2009 and August 2010. While this pandemic was smaller and less severe than that of 1918, it affected young, healthy people too, in some cases causing very serious illness and death. These people were not naturally immune to the new virus strain, which was different from those that cause influenza epidemics every winter. However, some people had been vaccinated and it would be interesting to know how long their immune response to the pandemic A(H1N1) strain lasted, and if it was comparable to that induced by the infection itself.

The researchers sought to answer these two questions by conducting

“the first ever study to compare vaccinated subjects with infected patients on the basis of so many immune response parameters”

The study was also original in that the researchers compared vaccinated subjects with infected patients. It included 50 volunteers who received a monovalent vaccine that targeted the pandemic H1N1 strain only and contained an adjuvant (designed to boost the effect of the vaccine, which had a low viral strain content). The vaccinated subjects were compared with 61 patients infected with A(H1N1) influenza. The infection was mild to moderate in 48 of the patients and severe in the remaining 13. The latter had to be admitted to hospital and treated with antiviral therapy after developing acute respiratory distress syndrome. The assessment was carried out one year after exposure to the virus or one year after vaccination.

The researchers showed first of all that the immune response induced by the vaccine was still strong one year later. They also identified similarities and differences between the three groups of people, depending on the immune response parameters. Thus, the effect of vaccination was similar to that of a moderate infection on several immune parameters. Both vaccination and moderate infection also caused a more significant migration of T cells to the mucosa.

The researchers then decided to investigate whether different immune response profiles existed, regardless of vaccination or infection status. They identified three profiles. The first one included a majority of vaccinated and moderately-infected subjects. Therefore, this research shows that different people have a different immune response capacity. It also confirms that influenza vaccination can induce an immune memory response of similar strength and quality to that produced by a moderate infection.

This study may have implications in terms of adjusting or optimising vaccination strategies. It could be used to improve vaccine efficacy assessment protocols. As a result, two parameters could be added to the antibody level: markers of T cell migration to the mucosa and the potential cytotoxic activity of one category of T cells (CD8).

Neisseria meningitidis, also called meningococcus, is a bacterium responsible for meningitis and septicemia[1]. Its most serious form, purpura fulminans, is often fatal. This bacterium, which is naturally present in humans in the nasopharynx, is pathogenic if it reaches the blood stream. Teams led by Dr. Sandrine Bourdoulous, CNRS senior researcher at the Institut Cochin (CNRS/Inserm/Université Paris Descartes), and Professor Xavier Nassif, Institut Necker Enfants Malades (CNRS/INSERM/Université Paris Descartes/Assistance Publique – Hôpitaux de Paris), have deciphered the molecular events through which meningococci target blood vessels and colonize them. This work opens a path to new therapeutic perspectives for treating vascular problems caused by this type of invasive infection. The study was published on June 1, 2014 in Nature Medicine.

Colonization of brain vessels by N. meningitidis Immunofluorescence analysis of a human brain section infected by N. meningitidis. The bacteria (red) have colonized the brain’s endothelial cells that express CD147 (green). (Cell nuclei are blue) © Nature Medicine

When the bacterium Neisseria meningitidis multiplies in the blood, it interacts with the endothelial cells that line the inside of blood vessels and adheres to their walls. In the skin and mucous membranes, meningococcal infection in the vessels creates hemorrhagic skin lesions (called purpura) due to bleeding in the tissues. Those can rapidly progress to a serious and often fatal form of the disease (purpura fulminans). In the brain, when meningococci adhere to the vessels they can pass through the blood-brain barrier[2], and cause meningitis when they invade the meninges[3].

Teams of researchers have deciphered how Neisseria meningitidis adheres to blood vessels, a step that underpins the bacterium’s pathogenicity. In blood vessels they have identified receptor[4] CD147, whose expression is essential for initial meningococcal adherence to endothelial cells. If this receptor is absent, N. meningitidis cannot implant in blood vessels and colonize them.

It is a well-known fact that the adherence process of meningococcal bacteria to human cells relies on pili, long filaments that are expressed by the bacterium and composed of different sub-units (pilins). However, the pilins specifically involved in N. meningitidis’ adherence to blood vessels had never been identified. The researchers have determined that two pilins, PilE and PilV, interact directly with the CD147 receptor. Without them, meningococci cannot adhere to endothelial cells.

Humans are the only species that can be infected by meningococci. To show in vivo that pilins PilE and PilV are essential for N. meningitidis to colonize the vascular network, the researchers used a mouse model, where the mice were immunodeficient and grafted with human skin, keeping the functional human vessels within the graft to reproduce in mice the infection stages as observed in human skin. These mice were then infected by meningococci naturally having pilins PilE and PilV, or meningococci in which the expression of these pilins had been artificially suppressed. The human blood vessels were only infected by meningococci displaying PilE and PilV, which confirms that these two pilins are essential to the bacterial colonization process.

The researchers also showed in an ex vivo[5] infection model that cerebral vessels and meninges, particularly rich in CD147 receptors, allow colonization by meningococci, unlike other parts of the brain.

The scientists now wish to develop a new type of vaccine (to complement those already available) that would block the interaction between N. meningitidis and the CD147 receptors, thereby stopping the bacterium from colonizing the vessels.

This study was made possible by support from the teams of Dr. Frank Lafont at the Centre d’Infection et d’Immunité in Lille (CNRS/INSERM/Institut Pasteur de Lille/Université Lille 1/Université Lille 2), Professor Fabrice Chrétien at the Unité Histopathologie Humaine et Modèles Animaux at the Institut Pasteur in Paris, and Dr. Eric Chevet in the Groupe de Recherches pour l’Etude du Foie (INSERM/Université de Bordeaux).

In an article which appeared in The New England journal of Medicine on 16 April, researchers from Inserm (Jean Mérieux-Inserm BSL-4 Laboratory, Lyon) and the Institut Pasteur have published their initial findings on the characteristics of the Ebola virus discovered in Guinea. Initial virological investigations enabled them to identify Zaire ebolavirus as the pathogen responsible for this epidemic. Performed in less than a month, sequencing of the complete genome and subsequent phylogenetic analysis show that the virus present in Guinea forms a clade (variant) that is distinct from strains previously identified in the Democratic Republic of Congo and in Gabon. Epidemiological investigations also linked the laboratory confirmed cases with the initial deaths recorded during the December 2013 outbreak.

©Inserm/ Guénet François

Ebola virus is a lethal, highly contagious virus for which there is presently no treatment. The symptoms are somewhat non-specific, and include fever, severe diarrhoea and vomiting. Between 30 and 90% of those infected with this organism die as a result.

On 2 April 2014, the World Health Organisation (WHO), in a communiqué published by the UN, reported that it had recorded 5 new cases of Ebola fever in Guinea. Since January, the total number of suspected and confirmed cases of Ebola fever in the present outbreak in Guinea is 127, with 83 deaths, according to WHO, which states that 35 cases were confirmed by laboratory testing.

The initial samples were analysed in Lyon in the Jean Mérieux-Inserm BSL-4 Laboratory directed by Hervé Raoul, Inserm Research Director, by the French National Reference Centre for Viral Haemorrhagic Fevers (attached to the Biology of Viral Emerging Infections Unit at the Institut Pasteur, directed by Sylvain Baize). A positive diagnosis was made.

A mobile BSL-4 laboratory was deployed in Guinea to provide assistance with diagnosis in the field. This mobile laboratory was developed as part of a European project, “EMP4,” coordinated by German researchers, and in which the Jean Mérieux-Inserm BSL-4 Laboratory is the French partner.

The researchers were able to analyse blood samples from 20 patients. Various tests were conducted by the scientists in order to establish a specific identity card for the virus.

Viral RNA was extracted from the blood samples, and then amplified and sequenced. These sequences were finally compared to 48 already known complete Ebola virus genomes. According to results, the analysis showed 97% identity with strains identified in the Democratic Republic of Congo in 1976 and 2007, and in Gabon in 1994 and 1996.

“These results demonstrate that we are facing the emergence of a new “form” of this virus in Guinea,” explains Hervé Raoul, Director of the BSL-4 Laboratory. This form is common to cases discovered since the month of December.

It would appear that the epidemic originated from a single introduction from animal to human.

Apart from the present epidemic, these results show that the endemic area for Ebola virus is greater than previously known, and that as a consequence, West Africa should henceforth be considered an area of risk for Ebola virus. Measures aimed at preventing transmission from wild fauna to humans and quickly identifying such events if there is a recurrence must be put in place in Guinea, as well as in neighbouring countries.

Hepatitis E causes acute or chronic inflammation of the liver. It is an emerging disease which can be fatal and has no known treatment. Vincent Mallet, Stanislas Pol and their team at the Institut Cochin (Paris Descartes University, Assistance Publique – Hôpitaux de Paris, CNRS, Inserm) and French hospital-based teams* have proved the efficacy of a treatment for patients suffering from chronic hepatitis E virus infection. Most patients can be cured when treated with ribavirin in monotherapy for 3 months. This work was published in The New England Journal of Medicine of 20 March 2014.

The hepatitis E virus is the biggest cause of viral hepatitis in the world and it is estimated that a third of the global population is at risk of being infected with this virus. Although most cases occur in developing countries, there has been an increase in the number of cases reported in France and other industrialised countries where the virus is spread to humans by contaminated, undercooked food and blood. Until now there has been no treatment for patients suffering from hepatitis E.

Like the other hepatitis viruses, hepatitis E causes inflammation of the liver. In its acute form, the infection can be fatal for elderly people, pregnant women and people with liver disease. In immunosuppressed people (transplant patients, patients on chemotherapy or people living with HIV), the hepatitis E virus infection can progress to chronic hepatitis and cause cirrhosis.

Developing a treatment for hepatitis E

Ribavirin is a drug prescribed for some types of viral respiratory infections in children and some forms of haemorrhagic fever. It is also used to treat hepatitis C. Vincent Mallet, professor at Paris Descartes University and hospital practitioner at the Cochin teaching hospital (AP-HP) and Nassim Kamar, professor at Paul Sabatier University and hospital practitioner at the Rangueil teaching hospital previously proved its efficacy for immunosuppressed patients suffering from a chronic hepatitis E virus infection. **

In this new study, data from 59 ribavirin-treated transplant patients suffering from hepatitis E was collected at 13 French transplant centres by Nassim Kamar (from the Rangueil teaching hospital in Toulouse) and Vincent Mallet. The researchers confirmed that “ribavirin prescribed as monotherapy for 3 months is an effective treatment for chronic hepatitis E virus infection”. For most of the patients (46 out of 59 patients), the virus remained undetectable 6 months after treatment was discontinued. A longer treatment period appears desirable for highly immunosuppressed patients or those with detectable traces of the virus in the blood after a month of treatment. The only identified and foreseeable side effect of ribavirin is anaemia which was managed in most patients without any difficulty.

“This work is the result of a genuine partnership between a large number of centres in France. It represents a major advance in this area” states Vincent Mallet. We hope our results will pave the way for further prospective studies designed to assess the efficacy of ribavirin for severe forms of hepatitis E virus infection, especially in countries in the southern hemisphere where the disease is a serious problem”.

* CHU Rangueil et CHU Purpan  Toulouse –  Hôpital Cochin, AP-HP), Pitié Salpêtrière (AP-HP) – Hôpital Saint Eloi de Montpellier – Hôpital Foch de Suresnes – CHU Lyon et CHU de la Croix Rousse de Lyon – Hôpital Paul Brousse (Villejuif, AP-HP) – Hôpital Lapeyronie de Montpellier – Hôpital Bretonneau et CHU Trousseau de Tours – CHU Bordeaux – Hôpital Claude Huriez et CHU de Lille – CHU Le Bocage de Dijon – CHU de Nantes

** Mallet V, Nicand E, Sultanik P, Chakvetadze C, Tesse S, Thervet E, Mouthon L, Sogni P, Pol S. Brief communication: case reports of ribavirin treatment for chronic hepatitis E. Ann Intern Med. 2010 Jul 20;153(2):85-9 et Kamar N, Rostaing L, Abravanel F, Garrouste C, Lhomme S, Esposito L, Basse G, Cointault O, Ribes D, Nogier MB, Alric L, Peron JM, Izopet J. Ribavirin Therapy Inhibits Viral Replication on Patients With Chronic Hepatitis E Virus Infection. Gastroenterology. 2010 Nov;139(5):1612-8).

A team of researchers coordinated by Prof Dominique Mazier (AP-HP, UPMC, Inserm Unit 1135, CNRS ERL 8255) and Dr Georges Snounou, Research Director at CNRS (UPMC, Inserm Unit 1135, CNRS ERL 8255) has succeeded in culturing the dormant hepatic stage of the malaria parasite, previously inaccessible to researchers. The initial results from this technical breakthrough have enabled the development of a new concept for the elimination of malaria relapse due to the activation of these dormant forms. It should enable the establishment of a new strategy for the management of this illness, which would involve combining a drug capable of activating the dormant parasite with one of the many drugs effective against the parasite.
These results have just been published in the journal Nature Medicine.

Present-day management of malaria

After the bite from an infected mosquito, the parasite that causes malaria reaches the liver, where it multiplies. It then propagates in the bloodstream, where its proliferation causes a potentially fatal illness. In some cases, including that of the parasite Plasmodium vivax in humans, a fraction of hepatic parasites may remain “dormant” for a year or more, hence their name, hypnozoites. These subsequently “wake,” or reactivate, over time, and give rise to a bloodstream infection. This feature is probably the source of the belief that malaria persists for life.

The hypnozoite constitutes a two-fold problem in terms of controlling/eliminating malaria—a greater number of cases needing treatment, and increased transmission. Unfortunately, primaquine, and a recently developed analogue, tafenoquine, the only drugs capable of killing hypnozoites, have adverse effects on the body that are sometimes serious. The identification of reliable alternative drugs therefore constitutes a public health emergency. Until now, the search for new anti-hypnozoite drugs has been based on observations made in humans infected with P. vivax, or in monkeys infected with a parasite related to P. vivax, Plasmodium cynomolgi.

Methodology

Through a collaboration with teams from the national IDMIT Center[1] at the French Atomic Energy and Alternative Energies Commission (CEA), and those of the Biomedical Primate Research Centre(BPRC) in the Netherlands, the team led by Prof Dominique Mazier and Dr Georges Snounou first succeeded in maintaining cultures of infected hepatic cells for 40 days, i.e. nearly four times longer than is usually achieved. The team then demonstrated the persistence of dormant stages throughout the duration of culture, with some reactivating over the time, thus mimicking what happens in humans. It also tested new drugs (discovered at the Institut Pasteur in Paris), which inhibit epigenetic factors, on these hypnozoites. These drugs act by targeting histone methyltransferases, and are able to kill the blood stage of the parasite. Paradoxically, one of them activated the hypnozoites. This unexpected result led the team to formulate a new strategy, “Wake and Kill,” which involves combining a drug that activates the dormant parasite with one of the many available treatments known to be effective against the multiplying parasite.

Results provide hope for the management of malaria 

Thanks to this methodology, developed via an international and multi-institute collaboration (Inserm, CNRS, CIMI, CEA, UPMC, AP-HP, Institut Pasteur Paris), it will now be possible to screen drugs in vitro for their anti-hypnozoite effect, thus limiting the need for animals. The challenge is to adapt this technique to screening a large number of compounds. In addition, the possibility of growing hypnozoites in culture will finally allow scientists to study this enigmatic parasite stage, described 100 years after the discovery of the causative agent of malaria by Laveran in 1880.