Study of Autophagy and the Effects of GALIG Gene Products in HIV-1 Infected Patients Who Are Under Antiretroviral Therapy Since Primary-infection, Chronic Phase, or Never Treated.

HIV Infections Clinical Trial

— ATGALIG-HIV  

Official title:

Study of Autophagy and the Effects of GALIG Gene Products in HIV-1 Infected Patients Who Are Under Antiretroviral Therapy Since Primary-infection, Chronic Phase, or Never Treated.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04160455
• Other study ID #: CHRO-2019-03
• Status: Recruiting
• Start date: November 7, 2019
• Est. completion date: November 7, 2039

Study information

• Verified date: January 2024
• Source: Centre Hospitalier Régional d'Orléans
• Contact: Aurélie DESPUJOLS
• Phone: 0238744071
• Email: aurelie.despujols[@]chr-orleans.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Little is known about autophagy during HIV infection. Recently, two different teams reported important dysfunctions of autophagy in HIV-infected patients despite sustained suppressive antiretroviral therapy. As altered autophagy is strongly linked to cellular senescence and chronic inflammation, two hallmarks of HIV-infected patients despite long-term suppressive antiretroviral therapy, it is important to improve our knowledge in the area. Our main objective is to determine whether all or part of mononuclear cell subpopulations (CD4+ and CD8+ T lymphocytes, and monocytes) exhibit a defect in autophagy function in a cohort of HIV-infected patients who are virologically-controlled (plasma HIV RNA <50 copies / ml) either spontaneously (i.e. HIV controllers or post-treatment controllers) or after they started antiretroviral therapy at different time points (i.e. at the acute or chronic phases), as compared with a control group (i.e. uninfected healthy blood donors).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: November 7, 2039
• Est. primary completion date: November 7, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

General criteria:

• Age >=18 years
• Man or woman
• Infected with HIV-1 (and not co-infected with HIV-2)
• Followed at Orleans' Regional Hospital
• Patient belonging to one of the predefined cohorts/groups (see below)
• Patient having provided a written consent Specific profiles of HIV-infected patients for the ATGALIG-HIV study: Cohort A: patients on suppressive antiretroviral therapy (HIV RNA <50 copies / ml for at least 4 years) initiated during the chronic phase, divided into 2 groups according to the

following criteria:

• group A1: CD4 count less than 500 cells / ml at the time of inclusion in the study
• group A2: CD4 count above 500 cells / ml at the time of inclusion in the study Cohort B: patients on suppressive antiretroviral therapy (HIV RNA <50 copies / ml for at least 4 years) initiated since the primary-infection (within 4 months after acute infection) Cohort C: patients with detectable HIV RNA, naïve of antiretroviral, but who have an

indication to start antiretroviral therapy, divided into the following 3 groups:

• group C1: HIV diagnosis made during primary infection (within 4 months of infection)
• group C2: HIV diagnosis made during the chronic phase (more than 1 year after contamination), with CD4 count above 200 cells/ml at the time of inclusion in the study
• group C3: HIV diagnosis made during the chronic phase (more than 1 year after contamination), with CD4 count less than 200 cells/ml at the time of inclusion in the study Cohort D: patients who have undetectable plasma HIV RNA (HIV RNA <50 copies / ml ) without antiretroviral therapy, either spontaneously (HIV controllers or elite controllers) or after treatment interruption (post-treatment controllers)

Exclusion Criteria:

• Patient unable, according to the investigator, to meet the requirements of the protocol
• Pregnant or lactating woman
• Patient with a history of inflammatory bowel disease, malignancy, intestinal ischemia, malabsorption or other gastrointestinal dysfunction that, in the judgment of the investigator, could interfere with the interpretation of the results.
• Presence of coagulation abnormality or unexplained bleeding history
• Treatment with oral or injectable anticoagulant (curative or preventive)
• Patient covered by Article L.1121-5 to L.1121-8 and L.1122-1-2 of the French Public Health Code (including minors and protected adults)
• Patient under guardianship or curatorship
• Patient who uncovered by French health insurance Patient participating in another clinical trial, evaluating a treatment

Related Conditions & MeSH terms

• Autophagy
• Communicable Diseases
• Galectins
• Highly Active Antiretroviral Therapy
• HIV Infections
• Infections
• Persistent Infection

Intervention

Biological:
• expression of a panel
Quantify, by droplet digital PCR, the expression of a panel of 7 genes (+ GALIG) involved in autophagy2 on sub-populations (CD4+ and CD8+ lymphocytes and monocytes) after their sorting using magnetic bead cell then RNA extraction Evaluate, on a functional test (as previously described1), whether the observed expression dysregulation is associated with a deregulation of the autophagic function, whether constitutive or induced.

Locations

Country	Name	City	State
France	CHR d'Orleans	Orléans

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Régional d'Orléans

Country where clinical trial is conducted

France, 

References & Publications (4)

Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet. 2013 Nov 2;382(9903):1525-33. doi: 10.1016/S0140-6736(13)61809-7. Epub 2013 Oct 23. — View Citation

Gomez-Mora E, Robert-Hebmann V, Garcia E, Massanella M, Clotet B, Cabrera C, Blanco J, Biard-Piechaczyk M. Brief Report: Impaired CD4 T-Cell Response to Autophagy in Treated HIV-1-Infected Individuals. J Acquir Immune Defic Syndr. 2017 Feb 1;74(2):201-205 — View Citation

Ipp H, Zemlin A. The paradox of the immune response in HIV infection: when inflammation becomes harmful. Clin Chim Acta. 2013 Feb 1;416:96-9. doi: 10.1016/j.cca.2012.11.025. Epub 2012 Dec 7. — View Citation

Serrano A, El Haddad S, Moal F, Prazuck T, Legac E, Robin C, Brule F, Charpentier S, Normand T, Legrand A, Hocqueloux L, Mollet L. Dysregulation of apoptosis and autophagy gene expression in peripheral blood mononuclear cells of efficiently treated HIV-infected patients. AIDS. 2018 Jul 31;32(12):1579-1587. doi: 10.1097/QAD.0000000000001851. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Quantify of a panel of genes involved in autophagy on sub-populations	Quantify by droplet digital PCR, the expression of a panel of 7 genes (+ GALIG) involved in autophagy on sub-populations (CD4+ and CD8+ lymphocytes and monocytes) after their sorting using magnetic bead cell then RNA extraction	Quantifications will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Primary	functional test on mononuclear cell subpopulations in the autophagy function	Evaluate on a functional test whether the observed expression dysregulation is associated with a deregulation of the autophagic function, whether constitutive or induced.	Quantifications will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Primary	Validation of the expression assays of genes involved in the autophagy function	Validate the expression assays of genes involved in the autophagy process and the statistical analyzes obtained on PBMCs on a validation cohort.	Quantifications will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Secondary	analyze regulatory markers on dysregulated gene promoters	To analyze regulatory markers on dysregulated gene promoters, we will analyze and compare the epigenetic marks (acetylation and methylation of histones, DNA methylation) overall and on the promoter zones of autophagy genes which present an alteration of expression.	Tests will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Secondary	quantify the reservoir of virus and ongoing viral replication	To quantify the reservoir of virus and ongoing viral replication, we will respectively evaluate the integrated viral DNA and the 2LTR circles levels.	Tests will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Secondary	analyze the phenotype of the PBMCs studied	To analyze the phenotype of the PBMCs studied, whether HIV positive or negative, we will evaluate, by analysis of surface markers in flow cytometry: Distribution of CD3+CD4+, CD3+CD8+, NK, B, NK-T and monocyte populations; Activation (HLA-DR and CD38 on T cells; HLA-DR, CD11b and CD16 on monocytes); Senescence (CD57+ on CD8+ T cells, CD7- on CD4+ T cells); Exhaustion (PD1 / CD279); Distribution of memories, naive and effector CD4+ and CD8+ lymphocytes (CD45RA and CCR7 / CD197); Proliferative capacity of PBMCs	Tests will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)
Secondary	Evaluation of the level of inflammation	To assess the level of inflammation, we will dose the inflammatory cytokines present in the patients' serum and controls.	Tests will be done once for all patients (Day 0), except in cohort C where they will be repeated after they started antiretroviral therapy (at month 1, 3, 6, 12 and 24)