Clinical trial NCT03191175: Inflammasome Activation Via Circulating Metabolites
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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Human Immunodeficiency Virus
Keywords: HIV
Inflammasome
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: ANRS, Emerging Infectious Diseases
name: Sidaction
name: Centre National de la Recherche Scientifique, France
First posted: 2017-06-19
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: HIV-infected patients with long-term suppressed viral load on cART

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.


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

Primary outcomes:
measure: Characterization of NLR (s) implicated in IL-18 up-regulation (inflammasome activation) in HIV
timeFrame: At baseline (D0)
Secondary outcomes:
measure: Characterization of circulating metabolites that active the inflammasome machinery
timeFrame: At baseline (D0)
measure: Non-AIDS related comorbidities
timeFrame: At baseline (D0)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Service d'immunologie
Study officials:
affiliation: Université de Bordeaux - ISPED - Inserm 2129 - CHU de Bordeaux
name: Linda WITTKOP, MD, PhD
role: STUDY_CHAIR
affiliation: University Hospital, Bordeaux
name: Isabelle PELLEGRIN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre National de la Recherche Scientifique, France
name: Benjamin FAUSTIN, PhD
role: STUDY_DIRECTOR
References:
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, Dechanet-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.
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.
citation: 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.
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, Thiebaut R, Pellegrin I; Groupe d'Epidemiologie 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.