PROJET HIDE INFLAMME & SEQ
Le projet HIDE INFLAMME & SEQ est porté par le CNRS et l’Institut de Génétique Humaine
CONTEXT & OBJECTIVES
Our working hypothesis is that in any individual, a particular combination of causes of immune activation results in a particular profile of immune activation that favours particular comorbidities. Our main model is efficiently treated HIV infection. In this disease, residual viral production, microbial translocation, coinfections, T4 lymphopenia, immune senescence, metabolic disorders and/or immune deregulation, particularly regulatory T cell deficiency may drive a persistent immune activation [1]. This ongoing immune activation potentially concerns all the actors of the immune system and is thought to fuel comorbidities including insulin resistance and metabolic syndrome, liver steatosis, atherothrombosis, neurocognitive disorders, depression, osteoporosis, frailty, kidney impairment, and certain cancers. Using 68 markers of immune activation and a double nonsupervised hierarchical clustering, we have identified in the ACTIVIH study 5 different profiles of immune activation in 120 persons living with HIV-1 (PLWHIV) aviremic under antiretroviral therapy [2].
Our objectives were to test whether the different immune activation profiles we have uncovered are linked to different causes of immune activation, whether they could fuel different comorbidities, and finally to test our working hypothesis in a general population.
In PLWHIV, we have shown that one immune activation profile was linked to microbial translocation [3], whereas another one was linked to residual viral production [4]. Moreover, we have observed that a specific immune activation profile, Profile #2, was correlated with high levels of insulinemia (odds ratio = 12,2, 95% CI 1.8-82.8) and triglyceridemia (odds ratio = 4,2, 95% CI 1.1-16.2b ) [2]. The fact that one characteristic of Profile #2 is an elevated plasma concentration of the soluble receptor I for TNF, a marker of production of an inflammatory cytokine known to inhibit insulin signaling, argues for a causative link between this immune activation profile and insulin resistance.
“La guérison du VIH/SIDA réclame encore un long effort de recherche. Il nous faut trouver des pistes nouvelles, qui découleront nécessairement d’une recherche fondamentale ambitieuse et risquée.”
Dr Monsef BENKIRANE
Directeur de l’Institut de Génétique Humaine et porteur du projet HIDE INFLAMME & Seq
RESULTS & PERSPECTIVES
As each of us potentially shares with PLWHIV many causes of immune activation, e.g., microbial translocation, the presence in our organism of infectious agents, immune senescence, metabolic disorders, regulatory T cell deficiency, which increase over aging, we tested our hypothesis in a general population. To this aim we recruited 150 persons affiliated to the Social Security and analyzed their immune system. Here again, we identified 5 different immune activation profiles [5]. Of note, one of these profiles, also characterized by high levels of soluble receptor I for TNF, presented elevated insulinemia, glycemia, triglyceridemia, and γ-glutamyl transferase, a marker of liver injury suggesting liver steatosis in these non-alcoholic volunteers. Of interest, using only three markers, we were able to determine whether a volunteer presented or not this immune activation profile linked to insulin resistance, with an error rate of 5% and a specificity of 99% [6].
All these data are compatible with our working hypothesis. Identifying with a few markers the immune activation profile of each individual might help in the future to personalize the screening and prevention of the immune activation-driven morbidities this person is at risk for. Moreover, a better understanding of the pathogenic mechanisms linking the different forms of immune activation to chronic diseases could lead to the identification of new predictive markers, and eventually to therapeutic targets.
PUBLICATIONS
1. Younas M, Psomas C, Reynes J, Corbeau P. Immune activation in the course of HIV-1 infection: Causes, phenotypes and persistence under therapy. HIV Medicine 2016,17:89-105.
2. Psomas C, Younas M, Reynes C, Cezar R, Portales P, Tuaillon E, et al. One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study. EBioMedicine 2016,8:265-276.
3. Younas M, Psomas C, Reynes C, Cezar R, Kundura L, Portales P, et al. Microbial Translocation Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults With Suppressed Viremia. Front Immunol 2019,10:2185.
4. Younas M, Psomas C, Reynes C, Cezar R, Kundura L, Portalès P, et al. Residual Viremia Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults Under Efficient Antiretroviral Therapy. Front Immunol 2021,12:663843.
5. Cezar R, Winter A, Desigaud D, Pastore M, Kundura L, Dupuy A-M, et al. Identification of distinct immune activation profiles in adult humans. Sci Rep 2020,10:20824.
6. Cezar R, Desigaud D, Pastore M, Kundura L, Dupuy AM, Cognot C, et al. Insulin resistance is linked to a specific profile of immune activation in human subjects. Sci Rep 2021,11:12314.