Homing, immune activation and infection

  • There is a growing amount of evidences in favor of causative links between a chronic state of overactivity of the immune system and the development of morbidities such as atherosclerosis, metabolic syndrome and type 2 diabetes, liver steatosis, neurocognitive disorders, osteoporosis, frailty, and even some types of cancer.
    HIV infection is a relevant model to explore these causative links. Our team is working on the chronic immune activation observed in efficiently treated HIV-1 patients (virologic responders), and on its consequences. Our working hypothesis in that each virologic responder may be characterized by one out of a few profiles of immune activation. Each of these immune activation profiles could be driven by specific causes, including persistent HIV production, microbial translocation, coinfections, CD4 T cell lymphopenia, immune senescence, and/or Th17/Treg dysregulation. Moreover, each immune activation profile might fuel specific comorbidities.
    Apart from driving chronic comorbidities, the persistence of immune activation in virologic responders may impede CD4 T cell recovery. We are currently exploring one mechanism linking monocyte activation to impaired CD4 T cell restoration.
    Besides immune activation, another major concern for virologic responders today is the persistence of HIV genome in the so-called « reservoir cells ». Various latency-reversing agents (LRA) have been proposed to force these reservoir cells to produce virions, with the aim of inducing their destruction. After a systematic screening of G-protein coupled receptors (GPCR) coexpressed in CD4+ T cells with the HIV coreceptor CCR5, we have identified GPCR whose activation may result in reversing HIV latency.

    figure 1 en
    Figure 1. Virologic responders present with different immune activation profiles. Heatmap showing the hierarchical clustering of the activation markers (vertical) as well as of the virologic responders according to their profile of activation (horizontal). Each Profile number is indicated

    To date, our research is funded by:

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    • Division of Hematology, McGill University Health Center, Montréal, Québec, Canada
    • Département des Maladies infectieuses et immunitaires, CHU Laval, Québec, Canada
    • INSERM U1065, Nice, France
    • Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
    • Hôpital Saint-Antoine, Département de Santé Publique, AP-HP, Paris France
    • Université Paris Descartes, Sorbonne Paris Cité; AP-HP, CIC Cochin Pasteur, Hôpital Cochin, Paris, France
    • INSERM, CIC 1417, Paris, F-CRIN, I–REIVAC, France


    Pierre Corbeau
    Corbeau Pierre
    Clement Mettling
    Mettling Clement
    Sandrine Gimenez
    Gimenez Sandrine
    Lucy Kundura
    Kundura Lucy


    Two-drug vs. three-drug combinations for HIV-1: Do we have enough data to make the switch?

    Moreno S, Perno CF, Mallon PW, Behrens G, Corbeau P, Routy JP, Darcis G

    2019 - HIV Med, 20 Suppl 4:2-12

    Request for full article30821898

    Increased Neutrophil Surface PD-L1 Expression in Tobacco Smokers: Consequences for Anti-PD-1 Treatment.

    Psomas C, Tuaillon E, Marin G, Reynes J, Corbeau P

    2018 - J Acquir Immune Defic Syndr, 80(2):e48-e49

    Request for full article30399041

    Immune activation, smoking, and vaccine response

    Younas M, Carrat F, Finge S, Desaint C, Launay O, Corbeau P; ANRS HB03 VIHVAC-B Trial Group

    2017 - AIDS, 31, 1, 171-173

    Request for full article27835620

    Plasma Level of Soluble ST2 in Chronically Infected HIV-1 Patients with Suppressed Viremia

    Younas M, Psomas C, Mehraj V, Cezar R, Portales P, Tuaillon E, Guigues A, Reynes J, Corbeau P, Routy JP.

    2017 - Open AIDS J., 11:32-35

    Request for full article28553430
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    Publications of the team

  • Immune activation in HIV patients under efficicent antiretroviral therapy: causes, types and consequences

    By measuring 68 cell surface and soluble markers of immune activation in 120 virologic responders, using a double hierarchical clustering analysis, we have shown that these patients may be sorted into 5 very different immune activation profiles (Profile 1 to 5). Our aim is now to identify the etiologic factors responsible for these 5 Profiles, as well as the morbidities that may be driven by them.
    We have already observed that an increase in the plasma level of lipopolysaccharide-binding protein, a marker of microbial translocation, is linked to immune activation Profile 4. We are now going to look whether other etiologic factors (HIV residual production, co-infections, immune senescence, Treg deficiency) are linked to other immune activation profiles.
    In terms of consequences, we have already observed that immune activation Profile 2 is strongly linked to hyperinsulinism, a mark of insuline resistance, with an odds ratio of 12,2 (95% CI: 1,8-82,9), as well as to marks of metabolic syndrome. Moreover, we have also noticed that immune activation Profile 3 is linked to Kaposi sarcoma development with an odds ratio of 4,2 (95% CI 95% : 1,2-15,3). Recently, we have analyzed immune activation in 85 additional virologic responders for whom neurocognitive disorders have been evaluated clinically and by functional imaging. We are now analyzing immune activation in 60 additional virologic responders for whom atherothrombosis will be measured by coronary scanner. We will also compare the prevalence of liver steatosis and fibrosis inbetween patients with different immune activation Profiles. This way, we will be able to search for correlations between some immune activation Profiles on one hand, neurocognitive dysunction, atherosclerosis as well as non-alcoholic fatty and fibrotic liver disease in another hand.
    From a basic point of view, we will study whether there is a causative link between Profile 2 and insulin resistance. To this aim, we will analyze whether the supernatant of peripheral blood mononuclear cells from patients with Profile 2 may induce insulin resistance in cocultures containing human adipocytes, by evaluating in these cells insulin-induced PKB phosphorylation. If it is the case, we will identify by cell sorting the subpopulation(s) responsible for this effect, and the factor(s) involved.
    We will also extend our work to healthy subjects. We believe that the same etiologic factors are responsible for an overactivity of the immune system over time in aging persons, that could pave the way for chronic morbidities such as metabolic syndrome, atherothrombosis, neurocognitive disorders, osteoporosis, and liver steatosis. Our objective is to identify an immune activation signature predictive of the development of each of these chronic diseases, and to understand the pathophysiological mechanisms linking immune activation to these morbidities in order to unveil new therapeutic targets.

    figure 2 en
    Figure 2. Link between immune activation Profile 2 and hyperinsulinemia. Odd ratios and 95% confidence intervals relating each Profile of immune activation to risk of hyperinsulinemia are presented.

    Monocyte-derived reactive oxygen species impair CD4+ T cell restoration in HIV-1 patients under efficient therapy

    We are also interested in another consequence of immune activation, that is the reactive oxygen species (ROS) overproduction we have observed in the monocytes of 50% of the virologic responders. We have shown that these ROS oxidate DNA in bystander cells, thereby creating double-strand breaks in their chromosomes, leading to DNA-PK and p53 activation. In primary CD4+ T cells cocultured with these activated monocytes, this phenomenon is responsible for apoptosis. The intensity of this phenomenon is inverssly correlated with CD4+ T cell recovery under antiretroviral therapy. Therefore, we think that this monocytic ROS overproduction is a cause of non immunologic response to treatment. We are now looking for the etiologic factor(s) responsible for this overproduction.
    We have observed the same pathophysiological pathway in all the non-treated HIV patients we have analyzed so far. In these persons, this phenomenon was even stronger. This raises the interesting possibility that ROS-mediated apoptosis might contibute to CD4+ T cell loss before antiretroviral treatment.
    Finally, the persistence over years of DNA damage induced by circulating monocytes, could favour oncogenesis. This is the reason why we will look for links between ROS overproduction and cancers in treated patients.

    figure 3 en
    Figure 3. In 50% of the virologic responders, monocytes release reactive oxygen species able to damage neighbouring cells, including CD4+ T cells, activating DNA-PK, p53 and apoptosis.

    Sphingosine-1-phosphate receptor 1 (S1P1) agonists as HIV-1 latency reversing agents

    Besides immune activation, another major concern for virologic responders today is the persistance of HIV genome in the so-called « reservoir cells ». A main objective in HIV research is to eradicate this reservoir. Various latency-reversing agents (LRA) have been proposed to force these reservoir cells to produce virions, with the aim of inducing their destruction.
    Sphingosine-1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor (GPCR) expressed in most immune cell types. It plays a critical role in T and B cell egress from lymph nodes. We have shown that S1P1 is coexpressed with the HIV coreceptor CCR5 in CD4+ T cells and is able to dimerize with CCR5. Moreover, we have observed that S1P1 stimulation induces the activation of the HIV promoter LTR via the transcription factor NKkB. Consequently, in culture medium containing sphingosine-1-phosphate, the presence of S1P1 enhanced the replication of HIV-1. In an in vitro model of latent HIV infection of peripheral blood or lymph node CD4+ T cells, we have been able to force reservoir cells to produce virions using the S1P1 ligand FTY720, a drug used to treat multiple sclerosis. S1P1 agonists could be therefore tested combined with other LRA in a shock and kill strategy of reservoir cells purge.
    Interestingly, we have identified two other GPCR that are also coexpressed with CCR5 in CD4+ T cells, dimerize with CCR5, and boost HIV genome transcription.

    figure 4 en
    Figure 4. Sphingosine-1-phosphate receptor 1 (S1P1) agonists boost HIV production. Agonist-induced S1P1 triggering activates the transcription factor NFkB, and consequently the HIV promoter LTR, resulting in an increase in viral expression (left pannel). S1P1 expression in target cells is responsible for a drastic enhancement of viral production (right panel)
  • Professional background

    Pierre CORBEAU, MD and PhD, Professor of Medicine
    Pierre CORBEAU performed his medical internship at the University Hospitals of Montpellier and Marseille in Cancerology, Infectious Diseases, Rheumatology and Immunology. He was Assistant Hospitalier-Universitaire and Maître de Conférence des Universités-Praticien Hospitalier at the University Hospital of Montpellier. He is currently Professeur des Universités-Praticien Hospitalier and Head of the Immunology Department at the University Hospital of Nîmes.
    He got his Master degree and worked for his PhD at the Marseille-Luminy Center for Immunology. He had postdoctoral scholarships at the Pasteur Institute, at the Institute of Cancer Research, University of London, UK, and at the University of California, San Diego, USA. He is currently Head of a Research Group at the Institute for Human Genetics, UMR9002, at Montpellier.
    He has taught in various Universities in France, for the Canadian Mentorat on HIV and at the University of California, San Diego, USA.
    He has worked as an MD and a researcher from the beginning on HIV infection.