Inflammasome Activation Via Circulating Metabolites

Study Overview
=================
Brief Summary
-----------------
The clinical challenges confronting patients with HIV has shifted over the past 10 years from acquired immunodeficiency syndrome to chronic diseases including atherosclerosis, neurocognitive disorders, and osteoporosis. Chronic low grade inflammation and monocyte activation have been consistently associated with comorbidities in HIV patients. Indeed, recent studies indicate that inflammatory mediators including IL-6, IL-1, sCD14 and s CD163 produced by monocytes, but not T-cell activation, predict Non-AIDS-related events in virologically suppressed HIV-infected persons treated with combined antiretroviral therapy (cART), highlighting the important role of monocyte activation in the occurrence of comorbidities in cART-treated HIV infected patients. Yet, the underlying molecular pathways of persistent monocyte activation in cART treated HIV-infected patients remains incompletely characterized. Our preliminary results: 1/ establish a link between the activation of the inflammasome, the increased of pyrimidine-derived metabolites and the cardiovascular risk in a cohort of elderly patients; 2/ show that treated HIV-patients are characterized by increased soluble IL-1b or IL-18 in their blood suggesting that the inflammasome pathway is activated. Objectives: In this study we will characterize the molecular pathways underlying persistent monocyte activation in treated HIV patients, through the implication of the activation of the inflammasome machinery: 1. Characterization of NOD like Receptor (NLR) expression in monocytes for IL-1b and IL-18 secretion (inflammasome activation); 2. Characterization of circulating metabolites that active the inflammasome machinery; 3. Evaluation of the link between the activation of the inflammasome, the increased of circulating metabolites and the non-AIDS related comorbidities.

Official Title
-----------------
Residual Immune Activation in HIV-infected Patients on Successful cART: Association Between Inflammasome Activation in Monocytes by Circulating Metabolites and Non AIDS Defining Comorbidities

Conditions
-----------------
Human Immunodeficiency Virus

Intervention / Treatment
-----------------
* Other: blood sample


Participation Criteria
=================
Eligibility Criteria
-----------------
HIV patients : Inclusion Criteria: Aged 18 years and above HIV-1 infected patients Enrolled in the CIADIS substudy of the ANRS CO3 Aquitaine cohort Patients receiving antiretroviral therapy HIV-1 RNA load below the detection limit of 40 copies/mL With a written and signed informed consent Exclusion Criteria: HIV-2 or HIV-1/HIV-2 co-infection Control patients : Inclusion Criteria: Aged 18 years and above Exclusion Criteria: HIV-1, HIV-2 or HIV-1/HIV-2 infection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV patients<br> | Other: blood sample<br>* 47ml blood (40 ml EDTA whole blood for Peripheral blood mononuclear cell (PBMC) and monocytes isolation and 7 ml for serum).<br>|
| Control patients<br> | Other: blood sample<br>* 47ml blood (40 ml EDTA whole blood for Peripheral blood mononuclear cell (PBMC) and monocytes isolation and 7 ml for serum).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of NLR (s) implicated in IL-18 up-regulation (inflammasome activation) in HIV | The metabolic profile in purified monocytes from HIV patients through label-free proteomics and assignment of metabolic targets The expression of NLR genes by quantitative Polymerase Chain Reaction (qPCR) in purified monocytes from HIV patients. | At baseline (D0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of circulating metabolites that active the inflammasome machinery | analysis of the ability of sera from HIV patients to activate inflammasome in HIV negative monocytes, and to induce IL-1, IL-18, or both secretion. metabolomic profile analysis of the ability of predominant metabolites in HIV patients to activate inflammasome. | At baseline (D0) | 
| Non-AIDS related comorbidities | metabolites of interest, inflammasome activation measured by IL-1b and IL-18 | At baseline (D0) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Inflammasome, HIV