Inflammasome Activation Via Circulating Metabolites

Human Immunodeficiency Virus Clinical Trial

— InflammoVIH  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03191175
• Other study ID #: CHUBX 2016/14
• Status: Completed
• Start date: July 3, 2017
• Est. completion date: December 20, 2017

Study information

• Verified date: September 2018
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: December 20, 2017
• Est. primary completion date: December 20, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes

Intervention

Other:
• blood sample
47ml blood (40 ml EDTA whole blood for Peripheral blood mononuclear cell (PBMC) and monocytes isolation and 7 ml for serum).

Locations

Country	Name	City	State
France	Service d'immunologie	Bordeaux

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Centre National de la Recherche Scientifique, France, French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS), Sidaction

Country where clinical trial is conducted

France, 

References & Publications (4)

Duffau P, Wittkop L, Lazaro E, le Marec F, Cognet C, Blanco P, Moreau JF, Dauchy FA, Cazanave C, Vandenhende MA, Bonnet F, Thiebaut R, Pellegrin I; ANRS CO3 Aquitaine Cohort Study Group. Association of immune-activation and senescence markers with non-AIDS-defining comorbidities in HIV-suppressed patients. AIDS. 2015 Oct 23;29(16):2099-108. doi: 10.1097/QAD.0000000000000807. — View Citation

Furman D, Chang J, Lartigue L, Bolen CR, Haddad F, Gaudilliere B, Ganio EA, Fragiadakis GK, Spitzer MH, Douchet I, Daburon S, Moreau JF, Nolan GP, Blanco P, Déchanet-Merville J, Dekker CL, Jojic V, Kuo CJ, Davis MM, Faustin B. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med. 2017 Feb;23(2):174-184. doi: 10.1038/nm.4267. Epub 2017 Jan 16. — View Citation

Ozanne A, Duffau P, Dauchy FA, Rigothier C, Terrien C, Lazaro E, Cazanave C, Lawson-Ayayi S, Bonnet F, Blanco P, Wittkop L, Pellegrin I; CIADIS sub-study in the ANRS CO3 Aquitaine cohort study group. Activation, senescence and inflammation markers in HIV patients: association with renal function. AIDS. 2017 May 15;31(8):1119-1128. doi: 10.1097/QAD.0000000000001461. — View Citation

Wittkop L, Bitard J, Lazaro E, Neau D, Bonnet F, Mercie P, Dupon M, Hessamfar M, Ventura M, Malvy D, Dabis F, Pellegrin JL, Moreau JF, Thiébaut R, Pellegrin I; Groupe d'Epidémiologie Clinique du SIDA en Aquitaine. Effect of cytomegalovirus-induced immune response, self antigen-induced immune response, and microbial translocation on chronic immune activation in successfully treated HIV type 1-infected patients: the ANRS CO3 Aquitaine Cohort. J Infect Dis. 2013 Feb 15;207(4):622-7. doi: 10.1093/infdis/jis732. Epub 2012 Nov 29. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	Non-AIDS related comorbidities	metabolites of interest, inflammasome activation measured by IL-1b and IL-18	At baseline (D0)