Viral infection : persistence, host response and pathophysiology
Coordinators : J. Izopet, B. Lagane
Our team specializes in the pathophysiology of infections with human immunodeficiency virus (HIV), hepatitis E virus (HEV) and zika virus (ZIKV). The major specific topic is the mechanisms underlying the persistence of virus in immunocompetent hosts (HIV, ZIKV) and immunocompromised patients (HEV). We are also working on how HIV enters host cells via chemokine receptors and the pathophysiology of HIV infection in the intestinal mucosa. Another aspect of our work is the route of transmission and pathogenesis of HEV and ZIKV during pregnancy. We have developed a number of specific model cell systems, including placental explants, extravillous cytotrophoblasts, hepatocytes, enterocytes, peripheral and tissue lymphocytes, together with systems based on clinical samples (intestinal tissue, early and term placenta, blood and biopsies from immunocompromised patients).
AXIS 1: HIV
Our laboratory develops a wide array of approaches in the fields of immunology, virology, molecular pharmacology and structural biology to study important aspects of the pathophysiology of HIV infection and AIDS. We are deeply anchored at the interface between basic and clinical science and benefit from the proximity of the Toulouse University Hospital. Our research comprises two main axes, which are themselves highly interconnected:
Mechanisms of HIV-1 entry and their pathophysiological consequences
PI: B. Lagane; Participants: P. Colin, B. Puissant, S. Raymond, M. Armani
We study the properties of interactions between the HIV-1 envelope glycoproteins (Env) and their cellular receptors, i.e. CD4 and depending on the viral tropism, the coreceptors CCR5 or CXCR4. We investigate how these interactions are regulated by factors of the target cells and the host immune responses and conversely, how the virus alters the cellular functions and immunity of the host. Finally we seek to characterize how the properties of viral entry shape the phenotypic properties of viruses and their role in different processes and stages of HIV-1 infection. These include first the very earliest step of infection, that is transmission of the virus. We seek to identify whether Env determinants lead to virus selection during transmission and favor the first steps in the establishment of infection in the host (WP #1). We also study how the properties of viral entry change over time in infection and by so doing contribute to pathogenesis of infection, in particular depletion of CD4 T-cells. In this regard, we investigate the role that the coreceptor natural ligands, i.e. several CC chemokines for CCR5 and CXCL12 for CXCR4, could play as a driving force of evolution of the properties of CCR5- and CXCR4-using viruses (WP #2). A third project is dealing with how the properties of Env interactions with cellular receptors regulate the cellular tropism of viruses, in particular their capacity to enter into macrophages. These cells play a critical role in the pathophysiology of HIV-1 infection. They form viral reservoirs and contribute to dissemination of the virus in tissues, in particular the central nervous systems, which has been linked to development of neurological disorders in patients. On this topic, we are currently pursuing our recent work (Colin, PLoS Pathog., 2018) on the role of CCR5 conformational heterogeneity in HIV-1 entry into macrophages, both in the context of infection by cell free viruses and through CD4 T-cells/macrophages contacts (WP #3). Lastly, our research deals with the signaling properties of primary Env/CCR5 interactions, which are thought to contribute to many aspects of the pathophysiology of infection. We speculate that signaling of Envs might depend on the CCR5 conformation(s) to which they bind, and that this process contributes to differences in the phenotypic properties between distinct HIV-1 strains. We are currently investigating this using BRET-based methods to monitor in real-time and in living cells the most upstream events of CCR5 signaling, i.e. interactions with G proteins and arrestins (WP #4).
HIV-1 persistence and impaired immune reconstitution in the gut mucosa despite antiretroviral therapy
PI: Prof. P. Delobel; Participants: M. Requena, C. Vellas, N. Collercandy
The gut mucosa remains substantially depleted of CD4+ T cells in HIV-1-infected individuals despite antiretroviral therapy, contrasting with much more complete restoration of CD4+ T cell counts in the blood and organized lymphoid tissues. The reasons for this dissociation remain largely unknown. The impaired reconstitution of the immune gut barrier is clinically relevant as it is associated with persistent microbial translocation events and chronic immune activation that lead to inflammation-related premature ageing in treated HIV-1-infected individuals.
We contributed to a better understanding of the mechanisms involved in the impaired immune reconstitution of the gut mucosa by describing alterations in the recruitment of CD4+ T cells, notably of Th17 cells, a cell subset playing a major role in mucosal defense against bacteria and fungi.
We found that small intestine epithelial cells produce reduced amounts of the CCL20 and CCL25 chemokines in HIV-1-infected individuals on antiretroviral therapy, leading to a defective recruitment of CCR6+ and CCR9+ immune cells, notably Th17 cells (Mavigner et al., J Clin Invest, 2012; Loiseau et al., Mucosal Immunol, 2016). By contrast, Th1 and effector memory CD8+ T cells could efficiently be recruited via alternative chemotactic axes, notably through CXCR3-mediated chemotactism (Loiseau et al., J Infect Dis, 2019). Further, Th1 and effector memory CD8+ T cells contribute to altering the recruitment of Th17 cells by IFN-g- and IL-18-mediated reduction of CCL20 production by enterocytes. By contrast, Treg cells remain efficiently recruited to the gut mucosa, leading to a sustained imbalance between Th17 and Treg cells, which is a hallmark of HIV-1 infection. We also found that Th22 cells could use the CCL28-CCR10 axis as an alternative to CCL20-CCR6 to migrate to the gut mucosa in treated HIV-1-infected individuals. But the restoration of Th22 cells is not sufficient in reducing persistent microbial translocation (Nayrac et al., Mucosal Immunol, 2020).
We also developed ex-vivo models to reproduce the gut mucosal microenvironment. We notably succeed in culturing primary human enterocytes, and driving their differentiation to reconstitute a polarized mature gut epithelium on transwells, allowing co-cultures with T cells. We also developed a model of gut tissue histocultures that could be infected ex vivo by HIV-1 to analyze the virus target cells in the gut microenvironment.
Another axis of our research focuses on HIV-1 persistence in the gut mucosa despite effective antiretroviral therapy. We developed several molecular tools allowing in-depth characterization of the HIV-1 reservoir in the blood and gut compartments, notably qPCR of residual RNA and DNA HIV-1 (tissue and cell-associated RNA, total and integrated DNA), ddPCR quantification of intact proviruses, single copy NGS of integrated proviruses (Illumina), analysis of the virus quasispecies genetic complexity by NGS (PacBio).
HIV-1 persistence in the gut leads to local and systemic chronic inflammation through sustained antigenic stimulation and immune effector cells recruitment to the mucosa. We are studying the role of IDO-1 in inducing Th17/Treg imbalance and T cell exhaustion, and the relationships between the gut microbiota and HIV-1 persistence in the gut mucosa.
Our research mainly relies on gut endoscopic samples obtain from cohorts of HIV-1-infected individuals and uninfected controls, recruited at Toulouse University Hospital in the ANRS EP44 and EP61 GALT studies (PI, Pr P. Delobel). Our research also relies on BSL3 facilities, flow-cytometric analysis and cell sorting, NGS, and bioinformatic cores.
AXIS 2: HEV
Pathogenesis of HEV infection
Role of gamma-delta T cells during HEV infections
PI : E. Champagne ; Participants: F. Abravanel, H. El Costa.
Hepatitis E virus (HEV, genotype-3) causes chronic infections in immunosuppressed patients. Viral persistence is linked to the immunological status of the patients but the determinants are largely unknown. We are committed to investigate γδ T cells in the context of human viral infections and we have observed that γδ T cells present activation and mobilization markers in immunosuppressed patients at the acute phase of HEV infection. We aim to clarify their role and if their activation is beneficial or detrimental. Our work is based on the analysis of patient blood samples collected at the acute, resolving or chronic phase of infection. Although rarely symptomatic, acute infections in immunocompetent individuals are sometimes diagnosed and allow investigating antiviral immunity in an immunocompetent context. γδ T cell reactivity against HEV-infected cells is also studied in in vitro models of infection and this has revealed that the virus is able to modulate the cytokine responses of γδ T cells to promote regulatory properties. Our objective is to determine if the immunomodulatory properties of HEV operate in vivo and can be targeted for therapeutic purposes.
Pathogenesis of Hepatitis E virus in high-risk patients: Role of the immune response.
PI : H. El Costa ; Participants : Q. Glaziou, N. Jabrane-Ferrat, F. Abravanel, J. Izopet.
HEV is currently the leading cause of acute viral hepatitis worldwide. The occurrence of severe clinical symptoms upon HEV infection increases during pregnancy, with aging and in immunosuppressed patients. Host immune response, rather than the virus itself, seems to be involved in the burden of HEV. Within this context, we recently showed that Effector memory CD8 T cell response elicits HEV pathogenesis in the elderly. Indeed, symptomatic infections were characterized by an expansion of highly activated effector memory CD8 T cells, regardless of antigen specificity. This robust activation was associated with qualitative and quantitative alterations in cytokine production. In addition, effector memory cells were endowed with high cytotoxic capacity and ability to rapidly migrate to the liver. Immune cell functions are tightly controlled by their energetic metabolism (including glucose, glutamine and fatty acids the pathways) which can be altered with age and following viral infections. Moreover, any alteration in one of the metabolic pathways leads not only to inefficient immune responses, but also to averse clinical outcomes. Thus, our ongoing studies aim at characterizing the response and the metabolic reprogramming of immune cells during HEV infection in the 3 high-risk groups of patients (pregnant women, elderly subjects and patients undergoing immunosuppressive treatment). Our goal is to determine the mechanisms responsible for viral clearance or occurrence of clinical complications.
HEV life cycle in hepatocytes and enterocytes
Role of autophagy in HEV budding from polarized hepatocytes
PI: S. Chapuy-Regaud ; Participants: J. Izopet, C. Allioux.
The budding of the quasi-enveloped form of the Hepatitis E Virus (eHEV) has been shown to depend on the exocytosis pathway. We developed a system of HEV culture on polarized cells which allows reproducing main features of hepatocytes (including polarized albumin and bile acid secretion and ZO-1 expression). In this system, eHEV is released in an infectious form mainly to the bile side; our preliminary results also show the role of autophagy. Our aim is to understand how exocytosis and autophagy are hijacked by eHEV for its egress and interplay at the molecular level. To this end, we study the characteristics of eHEV particles by proteomics and lipidomics and the intracellular events by shRNA knockdown of target proteins and imaging.
Replication of HEV in enterocytes
PI: J. Izopet ; Participants: O. Marion, M. Migueres, S. Lhomme.
The intestinal epithelium is the first barrier that HEV must cross before it can enter the portal bloodstream and gain access to the liver. The mechanisms by which HEV penetrates the gut epithelium tight-junction barrier are unknown. Animal model data indicate that the gut is an important site of extra-hepatic HEV replication and the human adenocarcinoma Caco-2 cell line is permissive to HEV. Our data from patients for whom ribavirin failed suggest that the gut could be an important virus reservoir. The role of intestinal M cells in HEV replication or transcytosis is unknown. Our preliminary data from cultures of primary small intestine epithelial cells polarized on transwell inserts indicate that enterocytes are permissive to HEV-1 and HEV-3 and release eHEV particles, preferentially from the apical side. Our main objectives are: (1) to study the localization of HEV in the intestinal mucosa after ex vivo infection of intestinal explants (2) to study changes in the permeability of epithelial cells induced by HEV infection (3) to determine the subcellular location of virus proteins (4) to evaluate the role of M cells in HEV replication or transcytosis (5) to study the effect of ribavirin and alpha interferon on virus production (6) to study innate immune signaling pathways following virus entry (HEV-1 vs HEV-3) and cytokine production.
AXIS 3: ZIKV
We are studying the replication of ZIKV in the genital compartment and at the maternofetal interface. We have evidence that ZIKV replicates differentially in a wide range of maternal and fetal cells, including decidual fibroblasts and macrophages, trophoblasts and umbilical cord mesenchymal stem cells.
Our latest results show that the virus persists in the semen of infected patients for a long time and that the spermatozoa bear viral antigens. We are now looking at the mechanisms the virus uses to persist in the genital compartment.
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Knowledge of the biology of RNA viruses and pathophysiological mechanisms.
Our research generates fundamental knowledge about chronic viral infections (HIV and HEV) and emerging infection (ZIKV), and clinical applications to combat these viruses whose pathophysiology remains unclear. Our links with the clinical departments of Toulouse University Hospital, with the technical platform of the CPTP and several international collaborations ensure the optimal development of original themes.
Our team members are committed to the teaching of students in the faculties of Medicine and Pharmacy; we also welcome Master and PhD students from both France and abroad to work and study in our laboratory.
Maud Mavigner (2008-2011)
Nawal Benhaji (2009-2013)
Adrien Saliou (2010-2013)
Johan Siewiera (2010-2014)
Claire Loiseau (2012-2015)
Charline Daguzan (2012-2015)
Hugo Barragué (2015-2018)
Jordi Gouilly (2015-2018)
Manon Nayrac (2015-2019)
Nicolas Capelli (2016-2020)
Qian Chen (2016-2020)
Post Doctoral Fellow:
Sokunthea Top (2013-2014)
Romain Gasser (2016-2018)