Twenty-five years. In effect in March 1983 that the term "AIDS" appears for the first time in the medical world, and in May the same year as the team headed by Professor Montagnier identify the virus. Therefore a sad anniversary for a disease that has claimed more than 28 million deaths since 1981. Although the epidemic appears to be stabilizing, 2.5 million people a year are infected with the virus, and it is estimated the number of infected in the world to 33.2 million. Because despite all the efforts of scientists, HIV remains a terribly tough enemy to destroy. The millions of people who fight tirelessly against the virus and live with in society knows that. The newspaper CNRS, partner Sidaction 28 to March 30,

chose to open its columns to researchers who are fighting the disease. HIV: scientists are always looking Fault When asked to researchers who attend the daily words that come to mind to describe the virus that causes infection of the deadliest since the influenza pandemic of 1918, the same adjectives fall lips: intelligent, complex unfair, devious, vicious. "We escaped!, says Frederic Tangy, director of the laboratory viral genome and vaccination" in Virology Department 1 of the Pasteur Institute in Paris. At each new progress that we have a scope 'Riddles wider opening before us ... "Satan HIV (see glossary at the end of article)! Without the bigger deals, we must acknowledge that this engeance from the chimpanzee and past in humans during the first half of the twentieth century is an enemy fiendishly tricky. Like any other virus, he knows dynamite and overwhelm the immune bodies it infects. Simon Wain-Hobson, director of the Unit Molecular Retrovirology of the same department, "" small "virus only nine genes and fifteen Protein," past master at "destroying the system meant to destroy" behaves as a mole (or rather an army of moles) infiltrated within our organization. It is to go for a family member, despite the mistrust that the environment, and then it sows panic on all floors break in to systems that manage the security of our health! "The metaphor speaks volumes about the duplicity and violence of the virus that attacks first, in most cases, the cells of genital or rectal mucosa. It is left to capture and transport by cells sentinel of the immune system (dendritic cells) to lymphoid organs (mainly lymph nodes). There, he met other cells (T lymphocytes), it infects, then duplicate and spread throughout the body. Soon, the organization, realizing it is attacked, triggers the response and delaying the advance of the enemy by mobilizing battalions of antibodies and activation of T lymphocytes CD8 + killers, a "response" that leads a dramatic drop in viremia (the rate of virus in the blood). The whole problem, said Olivier Schwartz, head of the unit Virus and immunity "in the Department of Virology Institute Pasteur, is that HIV" does nothing as multiply in the immune system when it is activated. "In the absence of antiretroviral treatment, HIV almost invariably managed to escape from his Cerberus and causes a chronic and asymptomatic infection that lasts several years. A phase in which "the viral load remains stable and low level of blood despite intense replication of the virus continues Philippe Benaroch, team" Transport and intracellular immunity "2 at the Institut Curie. The infected cells are quickly destroyed and renewed evidence that the immune system is able, for a long time, to contain the viral infection. "But do not stop completely. After long months of a heroic resistance, "the number of CD4 + T lymphocytes (the No. 1 target of HIV) that help other key cells of the immune system (the" killer T cells "CD8 + and B lymphocytes) to grow and counter attacks by the intruder, inexorably decreasing. AIDS appears when there is a collapse of both the number of CD4 + T cells (less than 400/mm3 blood, against more than 1 000 in normal times) and the response of T lymphocytes CD8 + killers, while viremia increases. " Tanks hidden in cells That is, crudely summarized, operating mode of HIV to deceive, disrupt and sabotage the immune system. A strategy of a terrible efficiency researchers try to understand the workings lower in order to improve the anti-HIV therapies. The role of dendritic cells in infection, in particular, is paramount. Nobody doubts today they represent one of the entrance of HIV in the body. "These cells presenters of the antigen" stimulate T cells, said Anne Hosmalin, team "Presentation of the antigen by dendritic cells "in the Department of Immunology Institute Cochin 3. They are called" presenters "because the immune system needs to be present fragments of the virus to activate immune responses wisely. Thus, the dendritic cells eat HIV, digest and break down into smaller fragments (epitopes) that will be trapped by molecules histocompatibility (HLA in humans) and presented to T lymphocytes Transmission orchestrated by a cascade of molecular events that Anne Hosmalin trying to decipher, knowing that this knowledge could be used to complement the arsenal of anti-HIV therapy. Once introduced into a T cell, HIV "alter the normal behavior of his" host ", continued Olivier Schwartz. Contact between the cell and antigen-presenting cells is disturbed, which modifies the immune response. "The person responsible for this upheaval? One component of HIV, the tiny protein Nef. "One axis of our research - which enjoy support among other Sidaction, the National Agency for Research on AIDS and viral hepatitis (ANRS), the Institut Pasteur ... - On the effects of infection on the biology of the cell. We strive to understand how particular Nef manages to disrupt the trafficking of certain molecules needed to start an immune response within a cell. A bit like a pyromaniac, having lit a fire, invested the operational center for firefighters diverting traffic relief, "said Olivier Schwartz. He stressed that this mechanism intended to weaken the defenses of the host cell and optimize replication of the virus "remains full of gray areas." Upon having forced the entrance of the fortress cell, HIV, a retrovirus to NRA has consistently incorporate its own genetic material in the genome of its host. A sleight of hand ( "integration") to deleterious effects. Each time an infected cell duplicates, it multiplies information of HIV at the same time as his. HIV also takes perverse pleasure to infect macrophages, other white blood cells specialized in the ingestion and digestion of all kinds of debris and microbes. "These cells are normally in their compartments swallowed and degradation pH acid which the virus should not resist, "explains Philippe Benaroch. But we showed that HIV manages to change this hostile environment a priority by putting race enzymes that need acid pH to operate and deteriorate. It creates a favorable environment for its survival and its multiplication. As a result, infected macrophages are a reservoir of viruses difficult to eradicate because hidden within these cells. "The immune system fails to detect or antivirals to kill them. Another unknown long reservoir is represented by a micropopulation of CD4 + T cells infected in which HIV is inactivated. "After inserting its genetic heritage in one of these cells, the virus enters a phase called" silent ", commented Simon Wain - Hobson. As it is off, it escapes the radar of the immune system (which mark the cells that produce new viruses) and reduces the window of antiviral intervention. "By studying the mechanisms responsible for establishing and maintaining such cell reservoirs," Monsef Benkirane, the Institute of Human Genetics (IGH) 4, Montpellier, may have found the parade to awaken these viruses "invisible" and force them out of their "hideout" is so that treatment can strike. "We have identified three cellular machinery that would be responsible for this latency resulting in a very low viral gene expression: the micro-RNA proteasome and the proteins heterochromatin. It is now important to develop molecules able to inhibit the cell machinery to induce viral replication in cells reservoirs. The goal: make the virus visible to the immune system and susceptible to antiviral drugs. " Therapeutic strategies What, precisely, therapeutic strategies at work to counter the actions of retrovirals most notorious? His arrival on the scene health and his long procession of victims have naturally "doped" the interest of the scientific community for the antiviral pharmacology. At present, doctors have more than twenty-five molecules to the war on AIDS. Among these "weapons", the reverse transcriptase inhibitors. They are targeting the HIV enzyme essential for the transformation of viral RNA molecules in proviral DNA. As for protease inhibitors, they block the action of an enzyme involved in the synthesis of viral proteins inside the cell, so that new virus products can not infect new cells. These two weapons are based on a simple principle: stop the stages of the devastating HIV replication. Unfortunately, if "the advent of highly active viral therapies for the treatment of patients infected with HIV has led both to contain the replication of this pathogen and improve the clinical condition of patients, they do not lead the total eradication of infection and induce ongoing emergence of resistant virus, "said Clarisse Berlioz-Torrent, Co, with Stéphane Emiliani, the team Molecular host-pathogen" department "Infectious diseases" of Cochin Institute. Without forgetting that the use extended to triple (the combination of three antiretroviral agents), very expensive, causing multiple secondary disorders. It should continue to act to isolate new antiviral agents is obvious. The most advanced research focuses on a third enzyme, integrase, it also strictly necessary for HIV replication and coming into action when the proviral DNA is introduced into the genome of the host cell. One of these new antiretrovirals, the Raltegravir, coupled with anti-HIV molecules more "classical", could play an important role for patients in treatment failure. Another area booming: the development of inhibitors of entry of virus into the cell, a terrible sorcerer in which the envelope glycoprotein (Env gp120, a large protein of HIV pegged to the envelope) arrives at clinging to a target cell (T cell, macrophage ...) identifying a receptor on CD4, as well as various specific coreceptors CCR5, and then to force the entry of cellular sanctuary. Several molecules are being studied to try to break the interaction between the virus and CCR5. Without forgetting the very original approach adopted by researchers from the Institute for Molecular Genetics in Montpellier (IGMM) 5 to counteract the cellular mechanisms used by this damn virus to multiply. The molecule they have developed (IDC16) blocks infection by preventing "splicing" (ie the maturation of HIV RNA, hence its replication). Better IDC16 is effective not only on different viral strains of laboratory but also viruses isolated from patients, even if they have become resistant to usual therapies. All these achievements already won - or about to be - on the virus. But victory is still far away. "One of the challenges posed by the development of new antiviral lies in the development of therapies capable of reversing the interactions between cellular and viral proteins," says Clarisse Berlioz-Torrent. Hence the interest shown by his team at the cellular protein TIP47. "We showed that this protein promotes the connection, within a host cell, two major structural components of HIV: the precursor Gag and envelope glycoprotein (Env), whose encounter triggers the production of new infectious virus completely, "says our researcher. If it prevents TIP47 to keep his role of "connector" is ipso facto reduced the infectivity of the virus products. "A discovery promises help to counter the ravages of HIV? It is not forbidden to think, provided to discover the molecule capable of thwarting the interaction Gag-TIP47-envelope. The track of vaccination In industrialized countries, the advent of powerful antiretroviral drugs and the introduction of triple have halted mortality to AIDS and the scourge transformed into a chronic infection treatment. Yet the vast majority of some 33 million people infected with HIV in 2008 live in underdeveloped areas and still has no access to molecules that have revolutionized the way home we inevitably fatal, there is no so long, infection. Translation: developing a preventive vaccine, easy to produce, distribute low-cost and ensuring strong and lasting immunity after one or two injections, is a priority in the fight against the global spread of AIDS. But all say quite clearly: if enormous progress has been made in understanding the immune system response to infection, and experts in vaccinology redouble their efforts on a global scale, no vaccine strategies developed date (sixty vaccine candidates are currently in clinical trial) has not yet been proven. The trail of live attenuated vaccine through genetic engineering, an operation to turn off the genes responsible for virulence of a virus, was quickly abandoned. It was too dangerous to be applied to humans, the virus attenuated AIDS back after a few years all of its pathogenicity. Ditto for the solution (very popular in the 1990s) using naturally occurring proteins on the surface of HIV as gp120. If they produce many antibodies capable of neutralizing the virus, these proteins are only effective against certain strains of HIV, the virus mutant cursed non-stop and foil this type of immune protection. Mobilizing killer T cells Over the past ten years, intensive searches are conducted in order to induce cellular responses by mobilizing "cytotoxic T lymphocytes. Is that these white blood cells, all out of the same center of production (bone marrow) and organized by followers of the commandos method strong ruthlessly eliminate the foreign pathogens within our cells. They can slow the replication of HIV and monitor the viral load, at least in the early stages of infection. Three large families of the "vaccine formulations" focusing on the actions of these elite troops to whisk immunity "cell" are developed, with varying degrees of success vaccines basis of "naked DNA" vaccines live recombinant vectors based on viral or bacterial and vaccines based on peptides (small fragments of protein synthesis). Principle of the first, easy to produce, relatively cheap and do not require cold chain to keep: injected into the body of a fragment of HIV DNA, reproduced by genetic engineering so that proteins of the virus are produced and used to stimulate the production of lymphocytes. Their power immunogen for the time being, unfortunately leaves to be desired. Live recombinant vaccines, in turn, result from the assembly of a virus previously attenuated, so innocent (as the smallpox virus or the canary that of avian pox), and some HIV genes to synthesize protein essential for stimulating the immune system. Review of courses? Overall disappointing. These carriers have so far failed to induce "answers T 'high amplitude or long term. Even more depressing: after three years of trials on several thousand volunteers, a live recombinant vaccines for HIV the most promising, the V520, composed of three genes of the virus synthetically produced and packaged in a weakened adenovirus ( the replica of a weakened cold virus), was abandoned because of its lack of effectiveness in September 2007, as decided by the American pharmaceutical company Merck. Yet another coup sword in the water that has affected the world of research, but does not have the moral Frederic Tangy. This researcher indeed bet on other vectors, namely that derived vaccine against measles. The vaccine "was administered to hundreds of millions of children since the 1960s, argues there. It is very well tolerated and effective vaccine is about 95% after a single injection. It is easily produced in large scale in many countries and distributed at low prices. These characteristics have led us to consider its use as a vehicle to immunize children and adolescents against both measles and AIDS. "The advantages of this vector in relation to his" rival "? Apart from its virtues and logistic practices, "its capacity, as shown by our results in animal models, to produce a lasting immunity. In addition, the measles virus and HIV have several properties, especially the fact that they both infect monocytes, macrophages and dendritic cells. Thus, a vector derived from measles virus that targets the protein of HIV in the same compartment as HIV itself has the advantage of inducing "danger signals" identical ". In short, a huge potential vaccine. But only clinical trials will further evaluate the safety and efficacy of this method. The path of lipopeptide In principle any different vaccines based lipopeptide capture the attention of Jeannine Choppin, team "Mechanisms of induction of immune response and vaccine design" in the Department of Immunology Institute Cochin. " The lipopeptide synthetic preparations are gathering fragments of HIV proteins and fatty acid (fat), she says. Our technology is designed to trigger the production of CD4 + T cells and CD8 + T, which could destroy cells infected with virus. Part lipid ensure the penetration of peptides in the "antigen presenting cells" that will initiate the immune response. And several peptides associated to increase the immunogenic potential of the preparation. "The ability to protect this" race "vaccine gives Does satisfaction? A question for the moment unanswered. "The results of the first protocols vaccine in humans showed T cell responses against fragments of proteins of HIV, said Jeannine Choppin, but the protection against HIV remains to be seen. We must therefore continue the development of these vaccines to amplify the cellular responses appropriate and, most importantly, keep them long term. "In a word, patience. Of patience, Ara Hovanessian, director of laboratory regulation of transcription and genetic diseases "of CNRS, would fail to develop a synthetic vaccine against HIV from the gp41, a major protein envelope viral. Why gp41? "Because we have identified this protein in a region tiny does not change regardless of the strain of HIV, he said. From there, we have designed and chemically synthesized the region. "And then?" In a series of experiments conducted on animals, injection of this replica has caused the production of neutralizing antibodies against most subtypes of HIV, while up to now, antibodies induced by other vaccines had not shone in their effectiveness since they were acting only against certain strains of HIV. "Pending verify the effectiveness on the macaque," this synthetic vaccine is a good candidate as a therapeutic vaccine, "says Ara Hovanessian. So much evidence that the search for a vaccine against AIDS progresses, that works worth, but remains an extraordinarily difficult undertaking. At least one of the major challenges of vaccinology for decades to come at the beginning of the twenty-first century. Philippe Testard-Vaillant GLOSSARY HIV Human immunodeficiency virus. Antiretrovirals (ARVs) Class of drugs used for treating infections associated with retroviruses such as HIV. AIDS Acquired immunodeficiency syndrome. Antigen Any substance recognized by a component of the immune system and causing his reaction. Retrovirus RNA A retrovirus is a virus whose genome is composed of RNA, a molecule very similar to DNA. It uses an enzyme, reverse transcriptase, to force the host cell to create viral DNA, which will then be able to enter the nucleus of the infected cell and integrate into chromosomes. Enzyme An enzyme is, in most cases, a protein that catalyzes a reaction and accelerates. Micro-RNA Small RNA molecules capable of blocking the synthesis of proteins. Proteasome Assemblage of molecules, among other things, the degradation of proteins Protein heterochromatin These proteins play a role in the organization of the genome and are involved in inhibition of gene expression. Candidate vaccine A candidate vaccine is a preparation vaccine being tested that could become a vaccine if all stages of testing (tolerance, immune responses induced) is conclusive. Vector A vector is a bacteria or virus non-pathogenic who introduced the immune system gene of the pathogen against which we want to immunize.