Inflammation, NK Cells, Antisense Protein and Exosomes, and Correlation With Immune Response During HIV Infection (INKASE)
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| ClinicalTrials.gov Identifier: NCT05243381 |
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Recruitment Status :
Recruiting
First Posted : February 17, 2022
Last Update Posted : September 7, 2022
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More than 90% of HIV-infected patients on antiretroviral therapy have an undetectable viral load. However, approximately 15% of these individuals do not sufficiently restore their TCD4 lymphocytes and have an unfavorable CD4/CD8 ratio despite good adherence and an undetectable viral load. Factors associated with immunovirological discordance include low CD4 cell counts prior to antiretroviral therapy, low CD4/CD8 ratios and positive cytomegalovirus (CMV) serology. These patients are at risk of significant non-AIDS events and mortality.
The anti-sense protein (ASP) is synthesized from the anti-sense strand of HIV-1. A cytotoxic anti-ASP response of CD8 T lymphocytes and anti-ASP antibodies have been demonstrated in infected patients. The conservation of the ASP gene in HIV-1, the virus responsible for the pandemic, suggests that its maintenance confers an advantage to the virus. ASP induces an inflammatory phenotype in surrounding cells. ASP can be externalized by the cell through its interaction with its cellular partner Bat-3. Once externalized in soluble or exosomal form, Bat-3 has the ability to regulate NK cell activity. During HIV infection, NK functions are disrupted, including those related to the expression of the Bat-3 receptor, NKp30.
In patients, the inflammatory phenomenon is strongly associated with chronic HIV-1 infection. The efficacy of antiviral treatments does not allow a complete normalization of either the immune system function or the inflammatory status of the patient. The observed effect of ASP on inflammation raises the question of the involvement of ASP in the maintenance of a chronic inflammatory state in patients under treatment. Increased inflammation has also been associated in HIV-infected patients with elevated plasma exosome levels. In patients undergoing treatment, chronic inflammation remains a major problem and an important source of comorbidities (cardiovascular in particular) and probably contributes to the immunovirological non-response in immunodiscordant HIV-infected patients.
It is hypothesized that ASP bound to its cellular partner Bat-3 in exosomes would disrupt the cytotoxic activity of NK cells, sustain inflammation and have a deleterious effect on immune reconstitution.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| HIV Infections | Biological: 20 ml blood test | Not Applicable |
The main objective of the project is to characterize the presence of ex vivo NK cell perturbations in patients living with HIV (PLHIV) with immunovirological discordance, in relation to ASP expression and plasmatic exosomes. The secondary objectives will be to identify new biological parameters to study and to establish mechanistic hypothesis explaining the results obtained during the study.
The study has a pathophysiological aim and is approved by the committee for the protection of individuals. Two groups of patients will be constituted: one group of PLWHIV with immunovirological discordance (20 patients) and the other group of PLWHIV with a good immune reconstitution (40 patients).
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 60 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Basic Science |
| Official Title: | Inflammation, NK Cells, Antisense Protein and Exosomes, and Correlation With Immune Response During HIV Infection |
| Actual Study Start Date : | April 22, 2022 |
| Estimated Primary Completion Date : | April 2023 |
| Estimated Study Completion Date : | April 2024 |
| Arm | Intervention/treatment |
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Immune non-responder patients
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Biological: 20 ml blood test
20 ml blood test |
Immune responder patients
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Biological: 20 ml blood test
20 ml blood test |
- Immune status of HIV-infected patients [ Time Frame: The day of inclusion ]CD4+ T-cell count
- HIV-1 Antisense protein [ Time Frame: The day of inclusion ]HIV-1 antisense protein expression level
- Impacts of exosomes on NK cell activity [ Time Frame: The day of inclusion ]Cytotoxicity activity and cytokines production (intracellular staining and qRT-PCR) during cytotoxicity assay
- NK cells phenotyping [ Time Frame: The day of inclusion ]Flow cytometry phenotyping: subpopulation, activation and exhaustion markers
- NK cells functionality [ Time Frame: The day of inclusion ]Natural and antibody-dependent cytotoxicity assays
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| Ages Eligible for Study: | 45 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patiens living with HIV over 45 years old
- At least 2 measurements of CD4+ T-cell and HIV viral load in the last 2 years
- HIV viral load < 50 copies/ml in the past 2 years
- For the immune non-responder patients : CD4+ T-cell count < 350 cells/mm3 on the last two tests
- For the immune responder patients: CD4+ T-cell count > 500 cells/mm3 on the last two tests
Exclusion Criteria:
- No antiretroviral treatment
- Immunosuppressive treatment
- History of cancer less than 5 years
- Pregnancy
- Breastfeeding mother
- Adult protected by law or patient under guardianship or curatorship
- Failure to obtain written informed consent after a reflection period
- Not be affiliated to a French social security system or a beneficiary of such a system
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05243381
| Contact: Alain MAKINSON, MH PD | +33467339510 | a-makinson@chu-montpellier.fr | |
| Contact: Charlotte SILVESTRE, PharmD | +33434359441 | charlotte.silvestre@irim.cnrs.fr |
| France | |
| La Colombiere Hospital | Recruiting |
| Montpellier, Herault, France, 34295 | |
| Contact: Charlotte SILVESTRE, PharmD +33434359441 charlotte.silvestre@irim.cnrs.fr | |
| Principal Investigator: | Alain MAKINSON, MH PD | UH MONTPELLIER | |
| Study Director: | Antoine GROSS, PHD | Centre National de la Recherche Scientifique, France |
| Responsible Party: | University Hospital, Montpellier |
| ClinicalTrials.gov Identifier: | NCT05243381 |
| Other Study ID Numbers: |
RECHMPL21_0518 |
| First Posted: | February 17, 2022 Key Record Dates |
| Last Update Posted: | September 7, 2022 |
| Last Verified: | September 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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Immune non-responder HIV-patients Immune responder HIV-patients HIV-1 antisense protein Exosomes NK cells |
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Infections Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Inflammation Disease Attributes Pathologic Processes Blood-Borne Infections Sexually Transmitted Diseases, Viral |
Sexually Transmitted Diseases Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases |