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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A, group A1 | 40 patients on suppressive antiretroviral therapy (HIV RNA <50 copies / ml for at least 4 years) initiated during the chronic phase : CD4 count less than 500 cells / ml at the time of inclusion in the study |
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| Cohort A, group A2 | 40 patients on suppressive antiretroviral therapy (HIV RNA <50 copies / ml for at least 4 years) initiated during the chronic phase: CD4 count above 500 cells / ml at the time of inclusion in the study |
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| Cohort B | 20 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) |
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| Cohort C, group C1 | 20 patients with detectable HIV RNA, naïve of antiretroviral, but who have an indication to start antiretroviral therapy: HIV diagnosis made during primary infection (within 4 months of infection) |
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| Cohort C, group C2 | 20 patients with detectable HIV RNA, naïve of antiretroviral, but who have an indication to start antiretroviral therapy: 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| expression of a panel | Biological | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| 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) |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
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Inclusion Criteria:
General criteria:
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:
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:
Exclusion Criteria:
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All HIV-1-infected adults (not co-infected with HIV-2), followed at the Infectious Diseases Department of Orleans' Regional Hospital and meeting the inclusion criteria, will be offered to participate in the study.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Aurélie DESPUJOLS | Contact | 0238744071 | +33 | aurelie.despujols@chr-orleans.fr |
| Name | Affiliation | Role |
|---|---|---|
| Laurent HOCQUELOUX, Dr | CHR d'orléans | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Orleans | Recruiting | Orléans | 45067 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24152939 | Background | 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. | |
| 23228847 | Background | 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. |
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Blood
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| Cohort C, group C3 | 20 patients with detectable HIV RNA, naïve of antiretroviral, but who have an indication to start antiretroviral therapy: 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 |
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| Cohort D | 20 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). |
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| 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) |
| 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:
| 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) |
| 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) |
| 29734217 | Background | 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. |
| 27787338 | Result | 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. doi: 10.1097/QAI.0000000000001201. |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
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