Inflammation, NK Cells, Antisense Protein and Exosomes, and Correlation With Immune Response During HIV Infection (INKASE)

September 5, 2022 updated by: University Hospital, Montpellier

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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

Enrollment (Anticipated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
    • Herault
      • Montpellier, Herault, France, 34295

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Immune non-responder patients
  • HIV viral load < 50 copies/ml in the past 2 years
  • CD4+ T-cell count < 350 cells/mm3 on the last two tests
Biological: 20 ml blood test
20 ml blood test
OTHER: Immune responder patients
  • HIV viral load < 50 copies/ml in the past 2 years
  • CD4+ T-cell count > 500 cells/mm3 on the last two tests
Biological: 20 ml blood test
20 ml blood test

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immune status of HIV-infected patients
Time Frame: The day of inclusion
CD4+ T-cell count
The day of inclusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HIV-1 Antisense protein
Time Frame: The day of inclusion
HIV-1 antisense protein expression level
The day of inclusion
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
The day of inclusion
NK cells phenotyping
Time Frame: The day of inclusion
Flow cytometry phenotyping: subpopulation, activation and exhaustion markers
The day of inclusion
NK cells functionality
Time Frame: The day of inclusion
Natural and antibody-dependent cytotoxicity assays
The day of inclusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Montpellier

Investigators

  • Principal Investigator: Alain MAKINSON, MH PD, UH Montpellier
  • Study Director: Antoine GROSS, PHD, Centre National de la Recherche Scientifique, France

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

April 22, 2022

Primary Completion (ANTICIPATED)

April 1, 2023

Study Completion (ANTICIPATED)

April 1, 2024

Study Registration Dates

First Submitted

January 24, 2022

First Submitted That Met QC Criteria

February 8, 2022

First Posted (ACTUAL)

February 17, 2022

Study Record Updates

Last Update Posted (ACTUAL)

September 7, 2022

Last Update Submitted That Met QC Criteria

September 5, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RECHMPL21_0518

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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