Biomedical research institute
     

    Physiopathology of acute SIV infection

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    The early stages of human immunodeficiency virus (HIV) infection remain difficult to study in humans, but are fundamental for the development of HIV-induced pathology.

    Simian immunodeficiency virus (SIV) infection in rhesus macaques is the experimental model presenting the closest physiopathology to human HIV infection. This model allows studying the events that occur during the first days following infection in tissues and in particular in the digestive mucosa, a crucial site both as a viral replication site and as a site supporting the initiation of the immune response.

    This part of the activity of the laboratory aims to study the early phases of SIV infection in macaque to identify the mechanisms involved in the establishment of the immune response and their physiopathological consequences. We explore the expression of cytokines, essential actors for the control of viral infections, in tissues and measure their physiological impact, whether for their direct antiviral action (especially for interferons) or indirectly for the stimulation of immune response (by stimulating its establishment or its effector capacity), but also for their pathological consequences.

    We are also involved in the analysis of the impact of IL-7-based therapy in chronically HIV-infected patients presenting poor immunologic responses during antiretroviral therapy. In this clinical study, we measured more specifically the effect of the therapeutic administration of IL-7 on the evolution of viral reservoirs.

     

     

    Type I Interferons in SIV physiopathology

    Principal investigator: Rémi Cheynier (DR Inserm)

    Contact remi.cheynier@inserm.fr - tel : +33 1 40 51 65 41

    Aims

    In primates, type I interferon family is composed of IFN-α, β, ε, κ and ω. The group of IFN-α is composed of 12 genetically very close proteins interacting with the same cellular receptor. These IFNs are rapidly produced in response to viral infections and participate in both the control of viral replication and the establishment of the adaptive immune response. Despite this genetic proximity, the conserved diversity of mammalian IFN-α suggests that they differ in their expression and/or function. However, the specificity of these different antiviral molecules is still poorly understood. This project aims, on the one hand, to identify the subtypes of IFN-α produced in the organs during the acute phase of SIV infection and on the other hand to analyze their function. In the SIVmac-infected macaque model, we have shown that some of the IFN-α subtypes expressed in the thymus during the acute infection phase exhibit significant antiviral activity. However, some of these cytokines also exhibit anti-proliferative activity on thymocytes, their production in the infected thymus leading to reduced thymic production in the early days of acute infection (Dutrieux et al., 2014).

     

    Questions

    We are exploring the anti-viral and anti-proliferative properties of the different human INF-α subtypes in order to propose alternatives to the INF-α2a subtype therapy currently used in clinics.

    In collaboration with the team led by Anne Hosmalin at the Cochin Institute, we are also studying the role of IFN-λ in the physiopathology of HIV-1 and HIV-2 infections.

     

    Physiopathology of acute SIV infection

    Principal investigator :  Anne Couëdel-Courteille (MCU Paris Diderot)

    Contact anne.couedel@inserm.fr - tel : +33 1 40 51 65 41

    Aims

    We have shown that during the early days of SIV infection in rhesus macaques, a transient increase of IL-7 production is observed in the digestive mucosa. This endogenous production of IL-7 leads to increased production in this organ of a set of chemokines capable of attracting numerous immune cells and in particular CD8+ T-cells and macrophages. This study allowed us to propose that IL-7 would be a danger signal that, produced early after infection, triggers the recruitment of immune cells to the site of viral infection and thus initiates the antiviral immune response (Ponte et al. 2017).

     

    Questions

    These results lead us to now look for intestinal mucosal cells capable of rapidly increasing their IL-7 production in response to infection and to explore the signals triggering this overproduction of IL-7.

    We are also evaluating the impact of increased IL-7 production during the first days of SIV infection on the establisment of viral reservoir and on SIV-specific immune responses.

    IL-7 expression in the ileal mucosa at day 10 of SIVmac infection. IL-7 appears in red, cytokeratin in green and cell nuclei in blue.

     

    Immunotherapeutic usage of IL-7

    Principal investigator : Magali Rancez (CR CNRS)

    Contact magali.rancez@inserm.fr - tel : +33 1 40 51 65 14

    Aims

    This part of the team's activity aims to evaluate the relevance of using IL-7 for therapeutic purposes in HIV-infected patients. Indeed, the well-known physiological properties of IL-7 in the homeostatic regulation of the T-cell compartment make it an ideal candidate to allow patients reconstructing a CD4 + T-cell compartment with a diverse repertoire. However, this cytokine could also stimulate viral replication, which may consequently, increase viral reservoir in patients.

    In collaboration with the Cythéris S.A., we assessed the consequences of IL-7 therapy in SIVmac-infected rhesus macaque and demonstrated that this well tolerated therapy allows spectacular reconstitution of T-cell populations through both peripheral proliferation of residual cells and, more importantly, through enhanced thymic activity (Beq et al., 2006).

    More recently, IL-7 was used in several clinical trials in HIV-infected patients presenting poor immunologic response to antiretroviral therapy, to stimulate the reconstitution of their T-cell populations. In these volunteers, we more specifically studied the impact of IL-7 therapy on the evolution of HIV reservoirs (Logerot et al. Submitted).

     

    Questions

    Like most therapies using recombinant proteins, treatment with IL-7 can induce the development of specific anti-IL-7 antibody responses. We therefore evaluate the consequences of anti-IL-7 neutralizing antibodies on T-cell homeostasis in the patients participating to INSPIRE 3 clinical trial.

     

    The team

    These projects were realized by Faten El Asmi (Post-doc ANRS), Jacques Dutrieux, Rosalie Ponte and Sandrine Logerot (PhD students Paris Diderot), Suzanne Figueiredo-Morgado (engineer INSERM), Bénédicte Charmeteau de-Muylder (technician INSERM), and Master students.

     

    Main publications

    Logerot S, M. Rancez, B. Charmeteau-De Muylder, S. Figueiredo-Morgado, S. Rozlan, G. Tambussi, S. Beq, A. Couëdel-Courteille And R. Cheynier. HIV reservoir dynamics in HAART-treated poor immunological responder patients under IL-7 therapy. AIDS. 2018 32(6):715-720.

    Ponte, R., M. Rancez, S. Figueiredo-Morgado, J. Dutrieux, V. Fabre-Mersseman, B. Charmeteau-de-Muylder, T. Guilbert, J.P. Routy, R. Cheynier and A. Couedel-Courteille, Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing. Front Immunol, 2017. 8: p. 588.

    Ponte R., V. Mehraj, P. Ghali, A. Couedel-Courteille, R. Cheynier and J.P. Routy, Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research. EBioMedicine, 2016. 4: p. 40-9.

    Dutrieux J., Fabre-Mersseman V., Charmeteau-De Muylder B., Rancez M., Ponte R., Rozlan S., Figueiredo-Morgado S., Bernard A., Beq S., Couëdel-Courteille A. and CheynierR. (2014) Modified interferon-a subtypes production and chemokine networks in the thymus during acute simian immunodeficiency virus infection, impact on thymopoiesis. AIDS. 28(8):1101-13.

    Ribeiro Dos Santos P., Rancez M., Prétet J.L., Michel-Salzat A., Messent V., Bogdanova A., Couëdel-Courteille A., Souil E., Cheynier R. and Butor C. (2011) Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation. PLoS One. 6(5): e19493.

    Parker R., Dutrieux J., BeqS., Lemercier B., Rozlan S., Fabre-Mersseman V., Rancez M., Gommet C., Assouline B., Rancé I., Lim A., Morre M. and Cheynier R. (2010) Interleukin-7 Treatment Counteracts IFNa Therapy-Induced Lymphopenia and Stimulates SIV-specific CTL Responses in SIV-infected Rhesus Macaques. Blood; 116 :5589-99.

    Beq S., Nugeyre M.T., Ho Tsong Fang R., Gautier D., Legrand R., Schmitt N., Estaquier J., Barré-Sinoussi F., Hurtrel B., Cheynier R. and Israël N. (2006) Interleukin-7 Induces Immunological Improvement in SIV-infected Rhesus Macaques under antiviral therapy. Journal of Immunology. 176: 914-922.

     

     Financial supports

    These programs are supported by the ANRS, SIDACTION, ANRT and Cytheris SA.

     

    Departments
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