An overview of research at the Institut Pasteur in Paris

Several teams are aiming to decipher the mechanisms of virus entry into target cells, its integration into the genetic heritage of the cell, the way in which it disrupts cellular functions in order to “reproduce itself” using the cell it infects, etc.

The molecular mechanisms involved in infection and dissemination of the virus in the organism, as well as the immune system’s response facing of this infection are currently under study (Virus and Immunity Unit, led by Olivier Schwartz). This work particularly focuses on HIV mechanisms for passing from one cell to another – which is the preferred method of propagation for the virus – or the antiviral defense barriers put in place by the cell itself.

In addition, research is being carried out on virus receptors, their distribution on the surface of the cellular membrane, their organization and the interactions with the viral envelope proteins that modify the environment of CD4 T lymphocytes, enabling the virus to start its replication cycle (Viral Immunology Unit, led by Fernando Arenzana-Seisdedos).

Also under observation is HIV-1’s method of replicating in macrophages, which are the main target of HIV after CD4 T lymphocytes (Gianfranco Pancino’s team in the Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi). Researchers have revealed that the activation of macrophages by certain stimuli inhibits multiplication of the virus. Lastly, other researchers (Elisabeth Menu’s team, in the Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi) are focusing on the mechanisms that restrict infection in trophoblastic placental cells, which are naturally resistant human cells. These cells could help control the transmission of HIV-1 in utero from mother to child.
 

One of the current difficulties in the search for a vaccine and effective therapies is the extreme variability of HIV that enables it to circumvent natural or therapeutic defenses. Viral strains from all over the world are analyzed to understand why and how HIV varies.

Multiple infections of cells infected with HIV-1 in vivo are under study (Molecular Retrovirology Unit, led by Simon Wain-Hobson). In particular, researchers have shown that a single cell can be infected by over one hundred viruses, but that very few of these will be integrated and therefore active. They are currently attempting to understand the keys to this phenomenon. Furthermore, variability and the development of forms of viral resistance to antiretroviral treatments are the subject of a major study within the International Network of Instituts Pasteur. Other projects are based on genetic recombination between viral strains, which is a significant cause of this variability (Matteo Negroni’s group in the Enzymatic Regulation of Cell Activities Unit, led by Michel Véron). These investigations particularly concern the impact of this mechanism on the variability of the viral envelope.
 

Researchers are concentrating on studying the transmission of the virus from mother to child, in conjunction with teams in Africa and Asia (Elisabeth Menu’s team, in the Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi).

Studies are under way on the prevention of transmission during pregnancy using antiretrovirals, in order to give a better understanding of the action mechanisms of these medicines at the level of the placental barrier, and to evaluate new molecules.  Other studies are based on natural transmission control mechanisms in utero and particularly on the role of maternal innate immunity during pregnancy, at the level of the endometrium. Researchers are also interested in the increase in risk of HIV-1 transmission in utero during viral or parasitic co-infections such as malaria, which is also endemic in certain African countries.

Understanding what naturally protects certain people is crucial for developing vaccines or treatments.

Researchers are interested in individuals, known as ENI (exposed non-infected), who are frequently exposed to the virus but remain uninfected, such as partners of HIV positive individuals who remain uninfected despite a history of unprotected sex over several years ("sero-discordant couples"), and intravenous drug users. They are looking to determine whether the natural defenses of these ENIs are the origin of their protection against HIV (the teams of Gianfranco Pancino and Daniel Scott-Algara, in the Regulation of Retroviral infections Unit, led by Françoise Barré-Sinoussi). These studies, carried out with the Institut Pasteur establishments in Cambodia, Bangui and Ho Chi Minh City, have already demonstrated the involvement of some innate immune cells: the Natural Killer cells. Research has also shown that, in certain ENI individuals, resistance mechanisms in cells that are targeted by HIV infection play a part in protecting against infection (Gianfranco Pancino’s team, in the Regulation of Retroviral Infections Unit). Researchers have in particular identified restriction mechanisms that affect either viral entry or the post entry stages in CD4 T lymphocytes.

In order to develop a vaccine, as well as to improve HIV treatments, it is necessary to go through a stage of understanding the physiopathology of the infection.

Scientists are studying the activation of killer cells in response to viral infection (Daniel Scott-Algara’s team, in the Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi). These NK (Natural Killer) cells are capable of causing the destruction of infected cells. Researchers are trying to gain a better understanding of their proliferation and their cytotoxic function.

Numerous analyses have been carried out in animals and in humans (monitoring of HIV positive individuals) in order to understand how the immune system is disrupted and to a large extent destroyed during the course of infection.

In particular, a team is studying the interactions between cytotoxic T lymphocytes (CTL) and HIV-1 (Candidate unit for Viral Immunopathology, led by Yves Rivière), via the analysis of immune system reconstitution in cohorts of infected patients treated with antiretrovirals.

Research is also focusing on other products of our natural defenses, interleukin-2 (IL-2) and interleukin-7 (IL-7) (Cellular Immunogenetics Unit, led by Jacques Thèze). These two cytokines play a major role in the anomalies in CD4 T lymphocytes observed in HIV+ patients. Studies undertaken to gain a better understanding of their mode of action are even more important in view of their immuno-therapeutic potential (see “Improvements in therapies”).

Last year saw the discovery of a mechanism by which the AIDS virus (HIV) impairs the immune response (Lymphocyte Cell Biology Unit, led by Andrès Alcover, and Olivier Schwartz’s Virus and Immunity group): researchers showed that the infection of T lymphocytes by the virus disrupted “immunological synapses”, which are established cell contacts that form between T lymphocytes and other cells of the immune system, that are essential for triggering immune responses.
 

Researchers are interested in the infection of African Green Monkeys by its SIV (Michaela Muller-Trutwin’s group, Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi). Levels of viral load as high as in humans or in Asian monkeys (macaque) have been observed in African monkeys with natural protection against AIDS. Unlike humans infected with HIV and macaques infected with SIV, African monkeys do not develop anomalies in T lymphocyte activation, and their T cells are not depleted abnormally. Recent studies indicate differences in the stimulation of their immune responses by the virus very early in infection. Understanding the mechanisms that are at the origin of these differences in animals could lead to the discovery of counter measures against HIV/AIDS in humans.

A study is under way of occasional individuals who have been infected with HIV-1 for many years, but who completely control the replication of the virus.
These HIV positive patients have been infected for over ten years, but have no detectable levels of the virus in their plasma, and maintain a high level of CD4 cells. They appear to control the infection in the absence of any therapy. Significant advances have been achieved in understanding this protection mechanism (see Cells that arrest the AIDS virus, Regulation of Retroviral Infections Unit, led by Françoise Barré-Sinoussi, in collaboration with Alain Venet, French National Institute for Health and Medical Research (Inserm), U 802, Faculty of Medicine Paris XI, Kremlin-Bicêtre). Other studies, in collaboration with the Kremlin-Bicêtre hospital, suggest that “central memory” CD4 T cells also have a part to play, because they are found in significant quantities in “HIV controllers” (Cellular Immunogenetics Unit, led by Jacques Thèze).

Antiretrovirals (ARV) control HIV replication. But these therapies must be taken lifelong, with onerous side effects, and a certain number of patients are in a situation of therapeutic failure. The Institut Pasteur is participating in studies aiming to enhance treatments for HIV+ patients by stimulating their immune response in a selective way.

Two Institut Pasteur laboratories (Cellular Immunogenetics Unit, led by Jacques Thèze, and the Immunoregulation Laboratory, led by Lars Rogge) are collaborating in clinical trials conducted by ANRS, using immune system molecules (IL-2 and IL-7) to try to restore patients’ defenses that have been impaired by the infection.

Rational research is being conducted to find HIV fragments, known as “epitopes”, capable of activating specific, targeted cellular immunity against the virus (Antiviral Cellular Immunity Unit, led by François Lemonnier). The first stage aims to identify viral sequences – potential epitopes – common to a maximum number of viral strains. We know that one of the problems in the development of an anti-HIV vaccine lies in the extreme variability of the virus, and one of the objectives of researchers is to develop vaccines that can protect against the majority of the viruses circulating worldwide. Prediction software enables epitopes to be identified and then tested on mice whose immune system has been “humanized”.

A candidate vaccine, “HIV-measles”, developed at the Institut Pasteur in the last few years (Viral Genomics and Vaccination Laboratory, led by Frédéric Tangy), should enter clinical trials very shortly.

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A team at the Institut Pasteur is developing a therapeutic candidate vaccine that could be used in patients who are already infected with HIV (Virology and Vectorology group, led by Pierre Charneau). A start-up company dedicated to the preparation of a clinical trial has recently been launched.

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