HIV – a complicated Foe

Viruses oase been proposed to be die most effective inhabitants des our planet.1 Why oase they been deswegen successful, and what renders a effective virus? the reasons space several, but central to viral success zu sein their ability zu propagate themselves zu a degree that is probably unprecedented an all des nature. Bei less 보다 one hour bei infected cell kann be hijacked zu produce thousands of copies of a viral genome.2

An extr prerequisite weil das a successful virus is the ability to evade or proactively suppress die host’s immune system. Some such as the human immunodeficiency virus (HIV) schutz alighted ~ above a devilishly effective strategy that allows them zu propagate their hereditary material und ensure that they space spared from perhaps debilitating immune responses an one fell swoop. Manfred Eigen, Chemistry Nobel Laureate 1967 zum his work in studying chemistry reactions, explains:


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Du schaust: Hiv wie steckt man sich an

Thus, HIV has actually evolved kommen sie infect those very cells von the immune system: helper t cells, macrophages and dendritic cells, that room responsible zum keeping it in check. This is not the only strategy bei HIV’s armoury, though. This ist a virus that transforms its hereditary code exceedingly rapidly3, basically representing a moving target both zum our very own immune system and for initiatives to design effective vaccines. Manfred Eigen, again, makes this point in his lecture from 1990.


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Why exactly ist rapid change deshalb hard zu deal with for our immune system? bei response kommen sie viral infection, our immune system produce so-called neutralising antibodies the bind to molecules on die virus surface ar and, as their nennen suggests, incapacitate famous function.4 Immunologist peter C. Doherty who got a share des the 1996 Prize zum Physiology or Medicine zum discoveries concerning cell-mediated immune defence, here defines why a swiftly mutating virus zu sein a problem for neutralising antibodies.

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Discovery and First Treatments

The infection that danach became known as AIDS (for acquired immunodeficiency syndrome) was zuerst described bei the us during the summer von 1981. Young, virtually always gay men were gift struck down with in affliction that was baffling doctors. While ns causative agent was notfall yet clear, what was obvious ist that those experiencing from the condition were having actually severe problems with dealing with routine epidemic – their immune system were in effect gift wiped out. In the absence von any hard charme about what precisely caused ns condition und how it was being spread, theories, some fantastical, und almost every hurtful, abounded. It was postulated the AIDS was a condition caused by the ‘lifestyles’ damit verbundenen with gay men or intravenous drug users. Von 1982, the had become clear that AIDS was being spread von bodily fluids, und soon after it was clear that heterosexuals and non-drug customers could deshalb contract it. The race was jetzt on zu identify the agent that caused it.5 Françoise Barré-Sinoussi shared für hilfe of the 2008 Nobel Prize bei Physiology or medizin with fellow akademie Pasteur researcher Luc Montagnier zum discovering HIV. An this excerpt from herstellung talk at die Lindau Meeting in 2010, Barré-Sinoussi speak about die history von HIV and the AIDS epidemic und highlights the lessons that tun können be learned from die discovery of HIV v a special focus on ns importance of multidisciplinary teams, von careful observation und of being an the right place at die right time.

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Françoise Barré-Sinoussi (2010) - HIV, a discovery Highlighting the global Benefit von Translational Research

Thank freundin very much for these very nice words des introduction.What I’d like kommen sie do in the following 20 minutes or so, it’s a short talk so I’m notfall going zu go right into detailsbut i like to give die example des HIV to zeigen the young researcherhow it’s important to make multidisciplinary and translational research.For HIV everything started really von observation, observation von our colleagues, epidemiologists und clinicianswho reported ns few cases von young homosexuals that were all presenting with serious immune deficiency.It is also based top top those observations that us had the idea that probably a virologe was ns cause des this freshly recognised epidemic.First cases were found an haemophilic patient indicating that probably a virologe was ns cause des this new emerging disease.And that is von our colleagues, ns clinicians the we schutz been mobilised at the Pasteur Institute.They came kommen sie us since some des them were following training und virology kurse at the Pasteur Instituteand they remember that Luc Montagnier und Chermann and myself were giving courses top top retroviruses.So this story yes, really started choose a an excellent opportunity at die point the it was in evolution des technologyand entstehen of research on retroviruses, everything anfang from opportunitiesand to be there at ns right momente with ns good technology.They recognise in France the erste cases von AIDS bei 1982, but at that time the zuerst human retroviruswas identified bei the vereinigt States by Robert Gallo’s group and these person retroviruses was causing ns cell leukaemia.The virus was infecting t cells dafür our colleagues and clinicians came kommen sie us weist Pasteurand asked even if it is we assumed that HTLV could be ns cause of AIDS.And our first reaction if ich remember correctly was kommen sie say this ist curious due to the fact that HTLV ist transforming the ns lymphocyte.And sie are just explaining kommen sie us that die cells space dying in the patient.So zu remember that bei other retroviruses like zum example feline leukaemia virus,the cat were dying of immune deficiency prior to dying of leukaemia.Progress an technology revolve out that few years before it was also the identification von what was called ns cell expansion factor,now recognized under the nennen of interleukin 2,that means we were able kommen sie grow in the laboratory t lymphocyte using these cellular factors.So it"s really this collective adventure started in the beforehand ‘80’s ...the clinician und we had a very decisive meeting at the Pasteur Institutewhen we had actually very straightforward question when, where und how zu look for which virus.I’m showing sie this slide for the young researchers, it’s also to keep an mind the we have to be careful around dogma.If we had started with ns idea the HTLV could be die cause of the an illness certainly ns approach that we schutz usedwill not schutz been successful.So that how die virus was identified in 1983, it was called punkt that time lymphadenopathy-associated virusbecause wherein we decide kommen sie look zum the virus was in the lymph node of the patients.And an additional important decision was zu decide kommen sie follow bei the culture von the cell obtained from ns left node,to follow in the culture every 3, 4 days in culture kommen sie find the end a reverse transitive activitywith ns enzyme which ist specific of this family of retroviruses.And that was deshalb an vital decision, when zu look.A couple of days after the culture we had actually the zuerst sign des disease virus in our supernatant.So automatically after this zuerst identification des the virologe we of kurse had bei mind to go kommen sie application as schon fast as possible.First des all us had an emergency, the emergency was kommen sie prevent blood transmission und transmission von HIV,this neu virus in haemophiliacs.So that way that us had to develop diagnoses tests und that was done really rapidlyand bei parallel these prüfung were used kommen sie make very large epidemiological surveyin order kommen sie make ns link bolzen the virus and the condition itself.Of course, these diagnoses tests were available kommen sie test,to protect against mother-to-child transmission and through information,counselling and so on, zu try deshalb to oase some impact on ns prevention des sexual transmission.We’re swiftly after the isolation of die virus, also we together,we mobilised our colleagues immunologists to work through us and to try zu identify die tropism of the virusand we very rapidly verified that ns virus was infecting preferential ECD4 lymphocyte, but so that ns CD4 molecule itselfwas a receptor of the virus, that was the basis of surveillance CD4 cells an the patients, and it’s still bei use today.We started very rapidly, after mobilisation des our colleagues und molecular biologists weist Pasteurto characterise HIV genome and to start to characterise a repetition cycle of the viruist into target cells.With an additional colleague we start to characterise a reverse phosphatase des the viruswith the idea that individuals des the reverse phosphatase probably important to develop therapies.Indeed, the zuerst antiretroviral drug that has been gezeigt with some efficiency was AZT,AZT was not sufficient as a therapy, yet AZT was the erste drug reflecting that we tun können prevent mother-to-child transmission.And you just heard from professor Montagnier the today, since 1996, we have a very efficient linked 3 therapy,also named as highly active antiretroviral therapy.We characterise ns genome of the virus and very quickly we discovered out the it was a very complicated organisation.You just saw on ns slide von Professor Montagnier,the organisation des the virus und very rapidly, as quickly as 1984, we knew that we had actually a really viable virus.But the identification of the genome of HIV was certainly the base to develop danach on a security testfor measuring ns viral load in the die geduld and deshalb to monitor resistance to antiretroviral therapy as well.Since then, since ns beginning von 1983 it has actually been a gewächs of progress des course in acknowledge and an changing biologyand pathogenesis, I in not going into the detail of every this progression that space reported top top this slide,I just let you know that of kurse we recognize that HIV originated from a transmission des the virus from monkey to humansalthough ns intermissions were really rare.And of kurse we have made a lot of progress bei our knowledge of the interaction des the virusand the host and leading to die development of progress an the knowledge of disease outcome.It has been a last of progress bei diagnoses und therapy however as you know regarding ns vaccine it has notfall been very successful.Vaccine research study started as soon as 1985/86 und still heute we don’t have any reliable vaccine.Another discovery punkt least weil das me was die fact that we will oase to challenge a global scale epidemic.And i had the gelegenheit personally kommen sie go as quickly as 1985 bei Central afri Republicand to realise the situation over there in those countries.So die theory began from ns discovery of the disease an the vereinigt States in 1981,followed von the discovery des the virus bei France, yet indeed we oase to face a globalen epidemicand we had really to learn how to work all together.I mentioned central African Republic, yet soon after in 1988 I deshalb started kommen sie go bei South east Asiaand it was there before die identification of the erste case von HIV in Vietnam an 1990.So it’s how really an additional story start, die story just how much ist importantand it’s our responsibility as a scientist kommen sie provide clinical evidencesto convince the political leaders and authorities zu make intervention in their countries.It’s important weil das providing scientific evidences to make multidisciplinary researchand kommen sie work so together through HIV communities, your participation i think is in example in the field von HIV.We have learned zu work altogether, scientists, doctors and activists.In ns developing welt it’s an extremely important kommen sie provide scientific evidences straight on siteand kommen sie make multidisciplinary research straight on siteto provide this scientific evidence locally bei order to develop interferenz through convincing the political leaders.So as ich heard yesterday students and young researchers are asking wie they room from negative resource restricted countries,whether they kann provide contribution, of prozess they kann sein contribute and they wollen contributeand there ist a gewächs of progress regarding science bei resource minimal countries in the field des HIV, ns sure an other fields.Those contribution from die country itself are very important for the decision,for die benefit des the public health an their very own country.Regarding HIV it has actually been progressive to access antiretroviral treatment in those resource limited countries.This zu sein a report of UNAIDS WHO belastung year, bei 2009 reflecting that us improve the access von treatment über 10between the end of 2003 und the ende of 2008 as you kann sein see on this slide.That means that roughly 40% des patients the are an need for antiretroviral treatment room treated.This ist bad und previous that recommendation kommen sie treat patients wie man they room 200 CD4 cell or less.We know heute that ns recommendation zu sein to act patients when there are more CD4 cells.So that method that all thus that has been excellent its already wonderful but its not sufficient hinweisen all.We know today that weil das 2 patients starting treatment there is 5 neu cases von infectionand still there zu sein 2.7 million neu cases des infection von year.Today we have more around 30 million des people living with HIV every over the world und still 2.5 million des deaths von year.So ns effort need to continue, the effort should continue,in particular we need to have future strategie to reduce the incidence von HIV-1 globally in the world.And of prozess it will be linked approaches.One approach ist based on behavioral changes, and for that information, education ist very important, des course.And as researcher we have to participate zu this info education routine as well.We oase biomedical tactics like condoms use, prefer circumcision that was proved to reduce the incidence,the risk von infection by 50/60% and we oase the antiretroviral treatment.We oase that already showing that therapy as prevention ist a pretty approach to reduce the risk des infection,that are indicating that approximately 90% reduction von the risk des transmitting the virus wie someone ist on treatment.One also, part of the approach to reduce ns incidence des infection zu sein certainlyto enhance everywhere in the welt social justice und respect des human rightsbecause if us want to treat earlier we need zu improve testing.And kommen sie improve experimentation we schutz to fight versus discrimination und stigmatisation des patients that are HIV positive.Because this zu sein one very important problem today zum someone to go zum the test is afraid about the eyes des the others.So this ist a combination von those approach, large based and biochemical approachand those other worries that us need zu work weil das the future.Of prozess another component for the strategy will be die vaccine.But ausblüten today we don’t have it.So we need to think about the neu therapeutic avoidance strategy weil das tomorrow.On that slide you oase 2 pictures, die picture des the situation, to be brief I mention die north,today us are notfall speaking any much more about AIDS mortality,we are speaking around chronic HIV infection, patients room living v HIV.In ns poor countries ausblüten we schutz AIDS mortality, you tun können see ~ above this slidethat an our countries an Europe, vereinigt States, ~ 5 years after infection ns mortality rateis without doubt exactly the same bei the general population as bei patients infected.In various other countries blieb we schutz 8 kommen sie 26% von patient mortality throughout the zuerst year of treatment initiation even.So that method that we oase to improve die access of treatment as ich said,we schutz to improve so the access von pregnant women zu antiretroviral treatment, only 45% of them oase access kommen sie treatment.But us have so on this slide part other difficulties that we schutz to face weil das the future.Professor Montagnier just mentioned ns viral latency bei HIV reservoir, this zu sein one an essential issuebecause we cannot stop the treatment und we schutz to schutz new therapeutic approachat least kommen sie reduce die size of the reservoir in the future.Another an important issue in HIV research ist to recognize better ns mechanismby which ns virus or viral component are inducing really rapidly inflammation activationand we recognize that there ist insufficient immune restoration even on antiretroviral treatment.We have bei our countries, bei Europe and United States neu complication, new complication relevant to lang term HAART,for instance you kann sein see ~ above this slide the 8% von patients that room on long term HAART are emerging cardiovascular disease.Some of them are developing cancers as stated before, lymphoma mostly yet other cancer as well, 15% of them.Some des them are arising liver disease, roughly 7%and we space seeing more und more neurological disorders an HIV patient on lang term HAART,aging disease, osteoporosis, Alzheimer choose disease.So we have to boost the situation regarding, acknowledge so why, why there ist such complication,what ist the role of the virologe or famous component, what zu sein the role of HAART in addition to viral components.So we blieb need additional research today.We certainly schutz learned as i said prior to from HIV pathogenesisbut we need to learn viel more, much more in particular throughout this really early phase des infection i m sorry is bei grey on mine slide.As you kann sein see during die very first, lets say week, i was ready to say first hours ~ infection.We oase already charme indicating the everything is decided, during let’s to speak the erste 96 hrs after exposure to ns virus.When i say everything zu sein decided in the HIV infection outcome,that way that really rapidly after ~ exposure to ns virus you schutz the epidemic itself,the dissemination von the virus an the body und the establishment as you kann see on the red part in the bottom of the slide,the establishment von HIV latency and HIV reservoir.We have also to learn far better what are the mechanics, like to explain the chronic immune activationand how zu control chronic immune activation, how to control die establishment of the reservoir.We recognize all of us here that we have a very complicated interplay between the virus, famous components and the host itself,of kurse we have learned about HIV diversity, we understand about the tropism des the virus,and variation in the tropism von the virus und the capacity von the virusand so we know that some des the variation are due to the virus,some von the variation are due so to host cell factors, involving in virus life cycle.We understand that die cells have intrinsic moving defence with restriction factors.It has been found like APOBEC TRIM5 und Tetherin, the tonnage one.And we know deshalb that ns virus and components des the virus oase immune suppressive capacity,they’re capable to induce abnormal activation signal.Some of the viral components that space capable zu induce abnormalities are ns envelope, ns nef protein, vpr und so on.And of course they möchte influence the immune response, the alternating immune solution as well as the adaptive immunity.And of kurse the genetic des the host is important zum the host immune solution as well.So we schutz to think about both ns genetic diversity des the host und the genetic diversity von the virus itself.There is distinct, innate and inflammatory response zu HIV, SIV infection bei the hostand we understand that certainly this distinctive responses zu sein depending von the dialogue,the dialogue between different actors von our immune defence.We have to consider the plasmacytoid dendritic cells, you know that space defence, several actors room playing a key role,like die plasmacytoid dendritic cells, like organic killer cells, T-cells and so on,of kurse B-cells weil das the production des antibodies.But you have to think about that ns virus zu sein coming, HIV und viral protein that recognise,that kann sein be recognised by plasmacytoid dendritic cells.But die response of the plasmacytoid dendritic cells through receptors, receptors favor TLR’sbut also maybe through other receptors zum example a record will kommen sie soonshowing the one restriction factor TRIM5alpha can be one receptor.So we schutz to consider die interaction between receptors and ligands.And follow to the diversity of both the receptor und the ligands you may schutz diverse inherent response.Innate solution involving pDC’s, NK cells and of kurse involving as a consequence different recruitmentthat activation of those cells, that space critical zum B-cells and T-cell response bei lymph node tissue,like lymph node as gezeigt on this slide.But we schutz to consider the diversity as i said to ns host receptors or ligands.Like zum example the NK receptor which space important, die KIR ,we know ns genetic polymorphism des the KIR zu sein influencing HIV infection.We know that HLADR is influencing of kurse HIV infection und we know that nef ist down regulating HLA, klasse 1 molecules.So we schutz to take together both the host and the virologe diversity an the distinctive innate and inflammatory responsethat renders then distinctive HIV, SIV an illness outcome.And we tun können learn native this varied spectrum of response.Indeed it is different modell that tun können be used to try kommen sie understand better die protection versus HIV or against AIDS,let’s zeigen very swiftly on this slide 2 of the modell on which we are working bei my lab und others are working as well.We have first HIV controllers or SIV controllers in the monkeys.Those are very interesting due to the fact that they regulate naturally die reservoir, they have low level of reservoir.And no detection von viral load in the monkey, organic control von the repetition von the virus.The other model zu sein the african primate, that are infected von SIV, 40/50% of them an Africabut castle do not develop the disease, why, due to the fact that they do notfall have mehr immune activation des the immune system,do notfall have abnormal inflammation.So we kann sein understand from both model und we room starting kommen sie understand indigenous both model.For instance HIV controllers, us know currently that lock are, most of them space HLA, B57, B27,we recognize that about hilfreich of them schutz very solid CD8 solution but so 50% of themwe can not explain von a strong CD8 solution but maybe by innate immunity or viral components.And so we are finding out from the monkey.So to finish i would say that we are discovering on HIV, yet I in convincedand ich like to glauben that we kann learn past HIV AIDS, HIV is a retrovirusand ich just stated that of kurse we have new difficulties with cancer, with aging disorders and HIV disease.We recognize that retrovirus in animals,we were very much studying at the end of ns ‘60’s together potential agent zum causing cancer und leukaemia.But heute HIV could be deshalb a tool kommen sie understand much better cancer und lymphoma.HIV may also be a tool to understand much better aging disorder,HIV may absolutely be a tool zu understand better immune defect and inflammatory und autoimmune malignancy.And the tonnage slide states that HIV AIDS since die beginning has actually been a wonderful scientific and human adventurebut it’s blieb continuing.We have new challenges, neu technology, neu concept kommen sie say und a neu generation of players.They wollen be responsible weil das the new discovery yet they would oase to keep bei mind,they oase to arbeiten with connection, connection with others as gezeigt on my slide,basic science along with clinical and operational research, basis science and different disciplineand also one discipline that ich mention on mine slide which ist not represented at Lindau zu sein a society economy called sciencewhich is in important teil also.And zu work together, all together with ns patients themselves.Thank sie very much.